Parasite 25, 10 (2018) © S.K. Panda and W. Luyten, published by EDP Sciences, 2018 https://doi.org/10.1051/parasite/2018008 Available online at: www.parasite-journal.org

REVIEW ARTICLE

Antiparasitic activity in Asteraceae with special attention to ethnobotanical use by the tribes of Odisha, India

Sujogya Kumar Panda1,2,* and Walter Luyten2 1 Department of Zoology, North Orissa University, Baripada-757003, India 2 Department of Biology, KU Leuven, 3000 Leuven, Belgium Received 6 November 2017, Accepted 3 February 2018, Published online 12 March 2018

Abstract -- The purpose of this review is to survey the antiparasitic plants of the Asteraceae family and their applicability in the treatment of parasites. This review is divided into three major parts: (a) literature on traditional uses of Asteraceae plants for the treatment of parasites; (b) description of the major classes of chemical compounds from Asteraceae and their antiparasitic effects; and (c) antiparasitic activity with special reference to flavonoids and terpenoids. This review provides detailed information on the reported Asteraceae plant extracts found throughout the world and on isolated secondary metabolites that can inhibit protozoan parasites such as Plasmodium, Trypanosoma, Leishmania, and intestinal worms. Additionally, special attention is given to the Asteraceae plants of Odisha, used by the tribes of the area as antiparasitics. These plants are compared to the same plants used traditionally in other regions. Finally, we provide information on which plants identified in Odisha, India and related compounds show promise for the development of new drugs against parasitic diseases. For most of the plants discussed in this review, the active compounds still need to be isolated and tested further.

Keywords: Asteraceae, Plasmodium, Trypanosoma, Leishmania, Odisha (India), antiparasitic drugs

Résumé --Activité antiparasitaire chez les Asteraceae avec une attention particulière pour l’utilisation ethnobotanique par les tribus d’Odisha en Inde. Le but de cette revue est d’étudier les plantes antiparasitaires de la famille des Asteraceae et leur applicabilité dans le traitement des parasites. Cette revue est divisée en trois parties principales: (a) littérature sur les utilisations traditionnelles des Asteraceae pour le traitement des parasites; (b) description des principales classes de composés chimiques des Asteraceae et leurs effets antiparasitaires; (c) activité antiparasitaire avec référence spéciale aux flavonoïdes et aux terpénoïdes. Cette revue fournit des informations détaillées sur les extraits d’Asteraceae rapportés à travers le monde et sur des métabolites secondaires isolés qui peuvent inhiber les parasites protozoaires, tels que Plasmodium, Trypanosoma, Leishmania et les vers intestinaux. En outre, une attention particulière est accordée aux Asteraceae d’Odisha (Inde), utilisées par les tribus locales comme antiparasitaires. Ces plantes sont comparées aux mêmes espèces utilisées traditionnellement dans d’autres régions. Enfin, nous fournissons des informations sur les plantes identifiées à Odisha et les composés qui seraient prometteurs en tant que médicaments candidats contre les maladies parasitaires. Pour la plupart des plantes discutées dans cette revue, les composés actifs doivent encore être isolés et testés plus avant.

Introduction Antiparasitic research people worldwide and are associated with significant morbidity and large economic impacts [88]. The lack of Parasite diseases are a major source of disease in both proper vaccines and the emergence of drug resistance humans and animals and result in significant economic make the search for new drugs for treatment and losses. Protozoan parasites threaten the lives of billions of prophylaxis more urgent, including from alternative sources like plants. In 2005, Pink et al. published a review *Corresponding author: [email protected]; emphasizing that new antiparasitic drugs are urgently [email protected] needed to treat and control diseases such as malaria,

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 S.K. Panda and W. Luyten: Parasite 2018, 25,10 leishmaniasis, sleeping sickness and filariasis [124]. 24,000–30,000 species [30]. The family has 12 subfamilies The discovery of quinine from Cinchona succirubra and 43 tribes, and is distributed worldwide [16], but is (Rubiaceae) and its subsequent development as an most abundant in the temperate and warm-temperate antimalarial drug represent a milestone in the history of regions. Most of the species are herbs and shrubs, while antiparasitic drugs from nature. The 2015 Nobel Prize in trees are fewer in number. Asteraceae have been Physiology or Medicine was awarded for the discovery of commonly used in the treatment of various diseases since artemisinin and avermectin, which fundamentally ancient times, as attested by classical literature. For this changed the treatment of parasitic diseases around the review, we collected literature from scientific journals, globe. Both compounds are natural products, once again books, theses and reports via a library and electronic showing that nature can be a powerful source of medicines. search (using databases viz. PubMed, Google Scholar and A breakthrough for the development of antimalarial drugs Scopus). Several researchers have systematically investi- was the identification of the sesquiterpene artemisinin gated Asteraceae for their therapeutic utility. More than from Artemisia annua (Asteraceae), which can even kill 7000 compounds have already been isolated, and 5000 multidrug-resistant strains of Plasmodium falciparum have been identified from this family, often associated with [3,62]. Several semisynthetic derivatives of artemisinin some bioactivity [3]. Members of the Asteraceae are (e.g., the water-soluble artesunate) have been developed claimed to have various properties: antipyretic, anti- and are used in clinical practice today [62]. inflammatory, detoxifying, antibacterial, wound-healing, There are three major protozoan parasitic infections, antihemorrhagic, antalgic (also for headaches), anti- caused by Plasmodium, Leishmania and Trypanosoma spasmodic, and anti-tussive, and have been considered species. Plasmodium is the most significant of the beneficial for flatulence, dyspepsia, dysentery, lumbago, protozoan parasites that infect humans. Found in tropical leucorrhoea, hemorrhoids, hypotension, and most impor- and sub-tropical regions of the world, malaria parasites tantly, some are hepatoprotective, antitumor and anti- threaten the lives of 3.3 billion people and cause 0.6– parasitic [68]. The majority of studies on Asteraceae 1.1 million deaths annually [70]. Six species of Plasmodium throughout the world have focused on chemical analysis are responsible for causing malaria in humans [144], with (nearly 7000 compounds already isolated). There are Plasmodium falciparum and Plasmodium vivax being the many papers on in vitro studies, especially on antimicro- most common and major causes. Leishmaniasis is caused bial, antioxidant and anticarcinogenic properties, using by Leishmania sp., generating 1–1.5 million new cases selected cells and crude extracts or purified compounds. In annually [104]. The disease is endemic in 98 countries and the few published reviews on pure compounds, the is one of the neglected tropical diseases where the majority structure-activity relations were studied as well as their of the affected individuals are rural, underprivileged, and mechanism of action. Despite the discovery of a large economically disadvantaged. African sleeping sickness number of compounds in Asteraceae around the world, (trypanosomiasis), is caused by two parasitic protozoans: and the reported antiparasitic properties of members of Trypanosoma brucei gambiense (West Africa) and the Asteraceae family, not many bioactivity studies on Trypanosoma brucei rhodesiense (East Africa) [15]. Asteraceae species have yet been carried out. In India, the African trypanosomiasis threatens the lives of approxi- family is represented by 900 species from 167 genera. mately 60 million people in sub-Saharan Africa and is fatal Due to their bioactive properties, plants from the if untreated [70]. Another species of Trypanosoma (T. Asteraceae family are commonly used in the traditional cruzi) is responsible for Chagas disease (American treatment of various diseases (Table 1). For instance, trypanosomiasis), and threatens the lives of millions Ageratum conyzoides has been commonly used in India primarily in Mexico, Latin America and the United States. including in the state of Odisha, where the plant is The World Health Organization estimates that 8– traditionally used for diarrhoea, dysentery, intestinal colic 10 million people are infected annually. There is also no [118] and malaria. This plant is well-known for the vaccine for Chagas disease and no clinical trials of new presence of phytochemicals such as alkaloids, coumarins, drugs are under way; current treatment depends on only flavonoids, benzofurans, sterols and terpenoids, with the two chemotherapeutics benznidazole and nifurtimox. following identified compounds: friedelin, various sterols (including b-sitosterol and stigmasterol), various flavo- noids, caryophyllene, coumarin, quercetin, as well as Medicinal uses of Asteraceae with special fumaric and caffeic acid [51]. Bidens pilosa is also found in reference to the tribes of Odisha (Orissa), Odisha, and is moreover widely used as folk medicine by India indigenous tribes of the Amazon in the treatment of malaria [13]. About 201 compounds comprising 70 ali- The family Asteraceae (Compositae) is also known as phatics, 60 flavonoids, 25 terpenoids, 19 phenylpropa- the daisy family, sunflower family or thistle family. noids, 13 aromatics, 8 porphyrins, and 6 other Asteraceae is derived from the term “aster” meaning “star” compounds, have been identified from this plant, as in Latin, and refers to the characteristic inflorescence with compiled previously [67]. However, the relation between flower heads composed of florets (small flowers), and Bidens pilosa phytochemicals and various bioactivities is surrounded by bracts [12]. The family Asteraceae is one of not yet fully established, and should become a future the largest families comprising 1600–1700 genera and research focus [7]. Blumea lacera is used for the treatment S.K. Panda and W. Luyten: Parasite 2018, 25,10 3

Table 1. Traditional uses of plants of the Asteraceae family

Plant1 Traditional uses by the tribes of Odisha Other parts of India/world Ageratum conyzoides (L.) L. Herb infusion is given for gastrointestinal As worm medicine in Cameroon [157]. ailments such as diarrhoea, dysentery and intestinal colic with flatulence [117,120]. Cold decoctions from the aerial parts are used to cure malarial fever (unpublished observations).

Bidens pilosa L. Fresh juice from the aerial parts is used for Juice form the root and whole plant is used intestinal worm infections, abdominal pain and for the treatment of malaria (Africa, China) stomach ache (unpublished observations). [142,157]. Whole plant is used by the Bukusu community of Kenya for tick prevention and control on livestock [159].

Blumea lacera (Burm.f.) DC. The tribes use fresh leaf juice of this plant for Leaf juice is used to kill worms in children the treatment of all kinds of fever, including by the tribes of Madhya Pradesh, India [136]. malaria (unpublished observations).

Calendula officinalis L. Cold decoction of leaf is used for amoebic and Flowers are used for the treatment of bloody dysentery (unpublished observations). intestinal worms and amoebal infections in pets and pigs in British Columbia, Canada [64].

Caesulia axillaris Roxb. Whole plant extract is given to cure malaria The whole plant is crushed and juice is [113]. extracted, which is given orally three times a day, along with curd to cure amoebic dysentery by the tribes of Madhya Pradesh, India [155].

Centipeda minima (L.) Root decoction is used for the treatment of all In China, decoction from whole plant is used A. Braun & Asch. kinds of fever [112]. Leaf decoction is commonly for malaria treatment. The seed or dried used for hookworm and roundworm aerial parts are used as a vermifuge and (unpublished observations). amoebicide (http://uses.plantnet-project.org/ en/Centipeda_minima_(PROSEA).

Eclipta alba (L.) Hassk. Treatment of malaria [112]. Leaf decoction is used by the Rakhain tribal healers of Chittagong Division, Bangladesh for the treatment of malaria [46].

Eclipta prostrata (L.) L. is a Treatment of malaria: decoction of dried leaf Infusion or juice of the plant mixed with synonym of Eclipta alba (L.) with tea leaf tincture is administered orally honey is given for the treatment of malaria Hassk. twice a day for five days [118]. by the tribal communities of Pakistan [86].

Elephantopus scaber L. Treatment of malaria: paste prepared from fresh Decoction from aerial parts is used to treat root is taken orally once a day for three days [118]. malaria by the tribes of Madagascar [86]. Juice of leaf is used in the treatment of malaria [53].

Sphaeranthus indicus L. Helminths: whole plant paste with a pinch of Root and seed powder is given orally to kill salt is taken as an anthelmintic [107]. intestinal worms in children [39]. Whole plant paste with a pinch of common salt is taken as an anthelmintic [61].

Tagetes erecta L. Cold decoctions of leaf and flower are used for Plants used by native Amazonian groups all kinds of worm infections and dysentery from the Nanay River (Peru) for the (unpublished observations). treatment of malaria [61].

Tridax procumbens (L.) L. Decoction prepared from leaves of Tridax Used for the treatment of malaria by the procumbens and Andrographis paniculata tribes of Ghana [59], and Kwale community (Burm. f.) Nees is used for the treatment of of the Kenyan Coast [90]. malaria fever (unpublished observations). 4 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 1. (continued).

Plant1 Traditional uses by the tribes of Odisha Other parts of India/world Vernonia anthelmintica (L.) Fruit powder is used in malaria fever, and for The seeds are used as an anthelmintic Willd. This name is a stomach ache during amoebic dysentery [81]. against parasitic worm (including tapeworm) synonym of Baccharoides Seeds are used as an anthelmintic, especially in infestations [4]. anthelmintica (L.) Moench. children (2-5 g with water on an empty stomach and Centratherum twice a day for three days) [111,112]. anthelminticum (L.) Kuntze

Vernonia albicans DC. Filariasis: powdered plant (10-20 g) is advised to – This name is a synonym of be consumed with 125 mL milk (mixed with Cyanthillium albicans (DC.) 5-7 cardamom fruits and 10 g sugar candy) once H. Rob. daily in the morning, on an empty stomach, for about three months [37]. Water-extract of the whole plant is used in the treatment of malaria [53].

Vernonia cinerea (L.) Less. Treatment of malaria; root paste is mixed with Leaf and bark are used by the tribes of This name is a synonym of honey and administered orally twice a day for Equatorial Guinea as febrifuge and vermifuge Cyanthillium cinereum (L.) three days [118]. The plant is also used for [2], while the tribes of Tanzania use it for the H. Rob. elephantiasis [120]. treatment of malaria [84].

Xanthium strumarium L. Coastal tribes of Odisha use crushed fresh fruit Tribes of Bannu district, Pakistan, use it for for the treatment of filariasis (unpublished the treatment of chronic malaria [154]. observations). 1 All taxonomic names were verified in the Global Composite Checklist database (http://compositae.landcareresearch.co.nz/Default.aspx) of all kinds of fever, including malaria, and contains topin, isodeoxyelephantopin, scabertopin, and isoscaber- phytocompounds such as fenchone, coniferyl alcohol topin, and lipids like ethyl hexadecanoate, ethyl-9, derivatives, campesterol, flavonoids, lupeol, hentriacon- 12-octadecadienoate, ethyl-(Z)-9-octadecenoate, ethyl tane, hentriacontane, a-amyrin, b-sitosterol and triter- octadecanoate, lupeol and stigmasterol [19]. Whole plant penes [7,80,105]. Calendula officinalis has found many paste of Sphaeranthus indicus with a pinch of salt is taken medicinal applications and contains various terpenoids as an anthelmintic by the tribes of Odisha [111]. The (sitosterols, stigmasterols, erythrodiol, brein, ursadiol and phytochemical studies of this plant suggest the presence of its derivatives; several triterpene glycosides like calen- eudesmanolides, sesquiterpenoids, sesquiterpene lactones, dulaglycoside A; glucosides of oleanolic acid, etc.), various sesquiterpene acids, flavone glycosides, flavonoid flavonoids (quercetin, isoquercetin, isorhamnetin-3-O- C-glycosides, isoflavone glycosides, sterols, sterol glyco- b-D-glycoside, narcissin, calendoflaside, calendoflavoside, sides, alkaloids, peptide alkaloids, amino acids and sugars calendoflavobioside, rutin, quercetin-3-O-glucoside and [125]. The essential oil from this plant has been well quercetin-3-O-rutinoside), coumarins, saponins and qui- studied with the documented presence of bioactive nones [87]. compounds like sphaeranthine, sphaeranthol, spharerne, Whole plant extracts of Caesulia axillaris are frequently methyl chavicol, ocimene, geraniol, and methoxy frulla- used by the coastal tribes of Odisha to cure malaria nolides [71]. Tagetes erecta is an ornamental plant of [107,113], but no scientific studies have yet been published Odisha and is often used by the tribes for the treatment of on this plant. Centipeda minima is widely distributed in various conditions such as anaemia, irregular menstrua- Odisha, and is frequently used by the local tribes for the tion, abdominal pain, colic, cough and dysentery. Like treatment of parasites [112], but no compounds responsi- Sphaeranthus indicus, this plant is also well known for its ble for its antiparasitic activities have yet been identified. phytoconstituents such as b-sitosterol, b-daucosterol, 7- Eclipta prostrata (synonym E. alba) is frequently used by hydroxy sitosterol, lupeol, erythrodiol, erythrodiol-3- the tribes for the treatment of malaria [113,130]. The plant palmitate, quercetagetin, quercetagetin-7-methyl ether, is well studied for its phytochemistry, with documented quercetagetin-7-O-glucoside, gallic acid, syringic acid, presence of compounds such as eclipline, b-amyrin, quercetin, ocimene and tagetone [135]. Tridax procumbens luteolin-7-O-glucoside, apigenin, cinnaroside, stigmasterol, has been extensively used in Ayurvedic medicine and is wedelolactone, columbin, triterpene glycosides and well-studied for its phytochemistry, with the presence of triterpenic acid [47]. Like Eclipta prostrata, Elephantopus compounds like 8,30-dihydroxy-3,7,40-trimethoxy-6-O- scaber is also frequently used by the tribes for the b-D glucopyranoside flavonol, apigenin-7-O-b-D-gluco- treatment of malaria [118]. This plant is also well studied side, pentadecane, b-sitosterol, stigmasterol, b-daucesos- for its phytochemistry with documented presence of terol and bis-(2-ethylhexyl)-phthalate [131]. Several sesquiterpenelactones such as elescaberin, deoxyelephan- species of Vernonia have been used in different traditional S.K. Panda and W. Luyten: Parasite 2018, 25,10 5 medicines all over the world. The tribes of Odisha most brevilin A from Centipeda minima and dehydrozaluzanin frequently use different species of Vernonia: V. anthel- C from Munnozia maronii were discovered and reported as mintica, V. albicans and V. cinerea. Seeds of Vernonia antiparasitic. Similarly, sesquiterpene lactones from anthelmintica are used as an anthelmintic, especially in Neuroleaena lobata are well established for the treatment children: 2-5 g with water on an empty stomach twice a of Plasmodium infections [28]. In this plant, structure- day for three days [111,112]. Fruit powder is used in activity relationship analysis revealed that germanocre- malaria fever, and stomach ache during amoebic dysen- nolide sesquiterpenes, like neurolenin A (EC50 = 0.92 mM) tery [81]. Powdered Vernonia albicans plant (10-20 g) is and B (EC50 = 0.62 mM), were more potent than furano- advised to be consumed with 125 mL milk (mixed with 5- heliangolides like lobatin A and B (EC50 = 15.62 mM and 7 cardamom fruits and 10 g sugar candy) once in the 16.51 mM), respectively, against Leishmania promasti- morning, on an empty stomach for about three months for gotes and Trypanosoma epimastigotes [28]. Based on the treatment of filariasis [37]. The aqueous extract of the ethnozoological studies (wild chimpanzees were observed whole plant is also used in the treatment of malaria [53]. to chew young stems of Vernonia amygdalina), anti- Root paste of Vernonia cinerea mixed with honey is plasmodial sesquiterpenes vernodalin and vernolide, administered orally twice a day for three days for malaria hydroxyverniladin have been isolated [60]. Oketch-Rabah [108]. Reports are also available on the use of this plant for et al. [101] observed that macrocyclic germancrane the treatment of elephantiasis [108]. Toyang and Ver- dilactone 16,17-dihydrobrachycalyxolide from Vernonia poorte [152] published a review article on this genus brachycalyx has both antileishmanial and antiplasmodial Vernonia (109 species) concerning its ethnopharmacology activity. and phytochemistry. Xanthium strumarium is a weed, Phenols are widely distributed in Asteraceae, and some widely distributed in Odisha, and commonly used as a have the ability to inhibit parasites. Gallic acid and its medicinal plant. Most of its pharmacological effects can be derivatives inhibit the proliferation of Trypanosoma cruzi explained by constituents like sesquiterpene lactones, trypomastigotes in vitro [58]. Higher activities were glycosides, phenols, as well as polysterols present in all observed for the gallic acid esters ethyl-gallate and n- plant parts. The bioactive compounds reported for this propyl-gallate, which had EC50 values of 2.28 and 1.47 mg/ plants are xanthinin, xanthumin, xanthatin (deacetylxan- mL, respectively, possibly due to increased lipophilicity. thinin), a toxic principle, namely a sulphated glycoside: Oketch-Rabah et al. [101] reported the antiprotozoal xanthostrumarin, atractyloside, carboxyatractyloside, activity from Vernonia brachycalyx (2́-epicycloisobrachy- phytosterols, xanthanol, isoxanthanol, xanthinosin, coumarinone epoxide and its stereoisomer). Both stereo- 4-oxo-bedfordia acid, hydroquinone, xanthanolides, caf- isomers show similar in vitro activities against feoylquinic acids, a-andg-tocopherol, thiazinedione and chloroquine-sensitive (CQ-S) and chloroquine-resistant deacetyl xanthumin, b-sitosterol, g-sitosterol, b-D-gluco- (CQ-R) strains for Plasmodium falciparum, as well as side of b-sitosterol; isohexacosane, chlorobutanol, stearyl Leishmania major promastigotes, with EC50 values of alcohol, stromasterol and oleic acid [52]. 0.11 mg/mL and 0.15 mg/mL for Plasmodium falciparum, and 37.1 mg/mL and 39.2 mg/mL for Leishmania major, respectively. Like phenols, flavonoids are extensively Miscellaneous antiparasitic properties of present in Asteraceae plants. Elford et al. [21] demon- Asteraceae and their phytochemistry strated that methoxylated flavonones artemetin and casticin act synergistically with artemisinin in vitro Over the past decades, a lot of research on antiparasitic against Plasmodium falciparum. Later, exiguaflavanone drugs of plant origin has yielded undisputable metabolites A and B, isolated from Artemisia indica (Asteraceae), of interest. Many plant-derived secondary metabolites of were shown to exhibit in vitro activity against Plasmodium Asteraceae have exhibited target-specific activity against falciparum. Plasmodium, Leishmania and Trypanosoma parasites The flavonoids can be classified into several subtypes: (Table 2). Plants from the Asteraceae family are widely flavone (1), flavonol (2), flavanone (3), dihydroflavonol used as medicines due to the presence of a broad range of (4), flavan-3-ol (5), flavan-3,4-diol (6), chalcone (a bioactive metabolites such as alkaloids (pyrrolizidine and structure with one opened ring), aurone, and anthocya- pyridine), flavonoids, phenolic acids, coumarins, terpe- nidine (with a positive charge on oxygen O-1). Except for noids (monoterpenes, sesquiterpenes, diterpenes, and these basic structures, flavonoids also exist in biflavonoid triterpenes), quinoline and diterpenoid types, triterpenoid and glycosidic form in the Asteraceae family. Perez- sesquiterpene lactones, pyrethrins, and saponins. Several Victoria et al. [122] suggested that flavonoids could affect sesquiterpenes have been reported as antiprotozoal since transport mechanisms in Leishmania. The C-terminal the discovery of artemisinin. The sesquiterpene lactone nucleotide-binding domain of a P-glycoprotein-like trans- parthenin is effective against Plasmodium falciparum in porter, encoded by the ltrmdr1 gene in Leishmania tropica vitro, with an EC50 value of 1.29 mg/mL [123]. Parthenin is and involved in parasite multidrug resistance (MDR), was capable of blocking parasite-specific targets responsible overexpressed in Escherichia coli as a hexahistidine- for glutathinonylspermidine and trypanothione synthesis tagged protein and purified. The Leishmania tropica from cysteine and glutathione precursors in both Leish- recombinant domain efficiently bound different classes of mania and Trypanosoma [32]. The sesquiterpene lactones flavonoids with the following relative affinity: flavone>- 6 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 2. Therapeutic uses of important plants of the Asteraceae family reported as an antiparasitic

Plant1 Plant part Pharmacological Preparation Organism tested Context Reference used of use Acanthospermum Whole plant Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] hispidum DC. Leishmania braziliensis Aerial part Antitrypanosomal Dichloromethane/ Trypanosoma brucei In vitro [10] Methanol/ Aqueous brucei

Achyrocline flaccida Whole plant Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] (Weinm.) DC.

Ageratina Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] pentlandiana (DC.) Leishmania braziliensis In vitro [69] R. M. King & H. Rob. Ageratum Whole plant Antiparasitic Organic (hexane, Trypanosoma brucei In vitro [98] conyzoides (L.) L. ethyl acetate, Trypanosoma brucei chloroform, rhodesiense methanol) and Trypanosoma cruzi aqueous extracts Leishmania donovani Plasmodium falciparum Whole plant Chagas disease Aqueous and Trypanosoma cruzi In vitro [149] ethanolic Whole plant Antileishmanial Aqueous and Leishmania amazonensis In vitro [149] ethanolic Leaf Antiparasitic Aqueous and Heligmosomoides bakeri In vitro [157] ethanol extract Leaf Antiparasitic Ethanol extract Rhipicephalus microplus In vitro [115]

Artemisia absinthium Flower Antiparasitic Di-ethyl ether Toxocara cati In vivo [163] L. essential oil Trypanosoma cruzi In vitro [74] Trichomonas vaginalis Trypanosoma cruzi In vitro [5] Leishmania infantum Leaf Schistosomicidal Dichloromethane Schistosoma mansoni In vitro [20]

Artemisia abyssinica Aerial part Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [94] Sch. Bip. ex A. Rich. Methanol brucei Dichloromethane Trypanosoma In vivo [25] congolense Aerial part Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [94] Methanol brucei

Artemisia afra Jacq. Leaf Antitrypanosomal Dichloromethane Trypanosoma brucei In vitro [82] ex Willd. rhodesiense / Trypanosoma cruzi. Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [94] methanol brucei Antimalarial Acetone Plasmodium falciparum In vitro [85] NF54

Artemisia annua L. Aerial part Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [94] Methanol brucei

Artemisia – Antileishmanial Aqueous Leishmania tropica In vitro [43] herba-alba Asso

Baccharis salicifolia Leaf Antileishmanial Ethyl acetate Leishmania braziliensis In vitro [27] (Ruiz & Pav.) Pers. extract

Baccharis uncinella DC. Leaf Antileishmanial Ursolic acid Leishmania infantum In vivo [49] S.K. Panda and W. Luyten: Parasite 2018, 25,10 7

Table 2. (continued).

Plant1 Plant part Pharmacological Preparation Organism tested Context Reference used of use Bidens pilosa L. Leaf Antimalarial Organic extracts Plasmodium falciparum In vitro [13] and fractions Antimalarial Organic extracts Plasmodium falciparum In vitro [102] Antimalarial Organic extracts Plasmodium falciparum In vitro [151] Antimalarial Organic extracts Plasmodium falciparum, in vitro & [63] Plasmodium berghei in vivo NK-65 (mice) Anthelmintic Ethanol extract Haemonchus contortus In vitro [36] Antileishmanial Crude extracts Leishmania amazonensis In vitro [35,49,151]

Blumea lacera Leaf Anthelmintic Alcoholic and Ascaris lumbricoides In vitro [119] (Burm.f.) DC. aqueous extracts Pheretima posthuma

Calendula Flower Antileishmanial Methanol (80%) Leishmania major In vitro [95] officinalis L. Antiparasitic Oleanolic acid Heligmosomoides in vitro & [145] and its glycosides polygyrus in vivo (mice) Centipeda Whole plant Antiparasitic Crude extracts Giardia intestinalis In vitro [164] minima (L.) and fractions A. Braun & Asch. Entamoeba histolytica Plasmodium falciparum

Chersodoma Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] jodopappa Cabrera Leishmania braziliensis Stem Antileishmanial Ethanol extract Leishmania donovani In vitro [27]

Cichorium intybus L. Leaf Anthelmintic Methanol:water Ascaris suum In vitro [160] Oesophagostomum dentatum

Cnicothamnus Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] lorentzii Griseb. Leishmania donovani Stem Antileishmanial Ethanol extract Leishmania braziliensis In vitro [27]

Conyza albida Willd. Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] ex Spreng. methanol rhodesiense, Trypanosoma cruzi

Conyza podocephala Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] DC. methanol rhodesiense, Trypanosoma cruzi

Conyza scabrida DC. Leaf Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] methanol rhodesiense, Trypanosoma cruzi

Echinacea purpurea Whole part Antileishmanial Ethanol extract Leishmania sp. In vitro [114] (L.) Moench

Eclipta alba (L.) Leaf Antimalarial Crude extract Plasmodium berghei In vivo [6] Hassk. Antileishmanial Crude extract Leishmania donovani In vitro [138]

Eclipta prostrata Leaf Anthelmintic Ethanol and Pheretima posthuma In vitro [11] (L.) L. activity aqueous extracts 8 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 2. (continued).

Plant1 Plant part Pharmacological Preparation Organism tested Context Reference used of use Leaf Anthelmintic Organic extracts Pheretima posthuma In vitro [50] activity Leaf Antileishmanial Saponin, Leishmania major, In vitro [56] dasyscyphin C Leishmania aethiopica, Leishmania tropica Whole plant Anthelmintic Organic and Haemonchus contortus In vitro [139] activity water extracts

Elephantopus Leaf Antitrypanosomal Organic extracts Trypanosoma brucei In vitro [165] scaber L. and sesquiterpene rhodesiense lactone

Helichrysum Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] nudifolium (L.) Less. methanol rhodesiense, Trypanosoma cruzi

Inula montana L. Aerial part Antileishmanial Methanol Leishmania infantum In vitro [73]

Jasonia glutinosa (L.) Aerial part Antileishmanial Acetone Leishmania donovani In vitro [156] DC.

Kleinia odora Whole plant Antiparasitic Ursane, Trypanosoma brucei In vitro [89] (Forssk.) DC. triterpenes Trypanosoma cruzi of lupane Leishmania infantum Plasmodium falciparum

Munnozia fournetii Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] H. Rob. (unresolved name) Leishmania donovani Stem Antileishmanial Ethanol extract Leishmania braziliensis In vitro [27]

Neurolaena lobate (L.) Leaf Antileishmanial Ethanol extract Leishmania mexicana In vitro [9] R.Br. ex Cass. Leishmania braziliensis

Oedera genistifolia Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] (L.) Anderb. & K. methanol rhodesiense, Bremer Trypanosoma cruzi

Ophryosporus Whole plant Antileishmanial Ethanol extract Leishmania In vitro [27] piquerioides (DC.) amazonensis Benth. ex Baker Leishmania braziliensis Pentzia globosa Less. Root Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] methanol rhodesiense /Trypanosoma cruzi

Perezia multiflora Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] (Humb. & Bonpl.) Leishmania braziliensis Less. Leishmania donovani

Pterocaulon Whole plant Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] alopecuroideum Chodat Leishmania braziliensis (unresolved name) Leishmania donovani S.K. Panda and W. Luyten: Parasite 2018, 25,10 9

Table 2. (continued).

Plant1 Plant part Pharmacological Preparation Organism tested Context Reference used of use Senecio clivicolus Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] Wedd. Leishmania donovani Stem Antileishmanial Ethanol extract Leishmania braziliensis In vitro [27]

Solanecio mannii Leaf Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [94] (Hook. F) C. Jeffrey methanol brucei

Sphaeranthus Whole plant Anthelmintic Ethanolic and Pheretima posthuma, In vitro [134] indicus L. aqueous extracts Ascaridia galli Leaf Macrofilaricidal Methanolic Setaria digitata In vitro [96] activity

Stevia yaconensis Whole plant Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] Hieron. Leishmania braziliensis Leishmania donovani

Tagetes erecta L. Root Antimalarial Organic and Plasmodium falciparum In vitro [41] aqueous extracts Flower Anthelmintic Organic extracts Pheretima posthuma In vitro [106]

Tithonia diversifolia Leaf Antitrypanosomal Dichloromethane: Trypanosoma brucei In vivo [103] (Hemsl.) A. Gray methanol brucei

Tridax procumbens Whole plant Antileishmanial Organic extracts Leishmania mexicana In vitro [75] (L.) L. property and (3S)-16,17 didehydrofalcarinol Methanol extract Leishmania mexicana In vivo [33] andincombination with Allium sativum Oxylipin, (3S)-16,17- Leishmania mexicana In vitro [75] didehydrofalcarinol

Vernonia Whole plant Anthelmintic Aqueous and Haemonchus contortus in vitro & [45] anthelmintica (L.) methanolic extracts in vivo Willd. Seed Anthelmintic Ethanolic extract Haemonchus contortus In vitro [44] Seed Anthelmintic – Haemonchus contortus In vivo [93] (buffaloes)

Vernonia auriculifera Root Antitrypanosomal Dichloromethane Trypanosoma brucei In vitro [29] Hiern rhodesiense

Vernonia hirsute Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] (DC.) Sch. Bip. ex methanol rhodesiense, Walp. Trypanosoma cruzi

Vernonia mespilifolia Leaf Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] Less. methanol rhodesiense, Trypanosoma cruzi

Vernonia natalensis Whole plant Antitrypanosomal Dichloromethane: Trypanosoma brucei In vitro [82] Oliv. & Hiern methanol rhodesiense, Trypanosoma cruzi

Vernonia oligocephala Leaf Antitrypanosomal Dichloromethane Trypanosoma brucei In vitro [82] Katt rhodesiense, Trypanosoma cruzi 10 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 2. (continued).

Plant1 Plant part Pharmacological Preparation Organism tested Context Reference used of use Vernonia squamulose Stem Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] Hook. & Arn. Leishmania braziliensis Leishmania donovani

Werneria nubigena Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] Kunth Leishmania donovani Stem Antileishmanial Ethanol extract Leishmania braziliensis In vitro [27]

Xanthium catharticum Leaf Antileishmanial Ethanol extract Leishmania amazonensis In vitro [27] Kunth Leishmania donovani Stem Antileishmanial Ethanol extract Leishmania braziliensis In vitro [27]

Xanthium strumarium Leaf Antitrypanosomal 50% ethanolic Trypanosoma evansi In vitro [147] L. extract and in vivo Fruit Antimalarial Methanol: water Plasmodium falciparum In vitro [153] extract strain FCR-3 1 All taxonomic names were verified in the Global Composite Checklist database (http://compositae.landcareresearch.co.nz/Default.aspx)

flavanone>isoflavone>glucorhamnosyl-flavone. The af- Leishmania tropica (Table 3). A sesquiterpene lactone finity was dependent on the presence of hydroxyl groups (deoxyelephantopin) was isolated by Zahari et al. [165] at positions C-5 and C-3, and was further increased by a from E. scaber and proved active against Trypanosoma hydrophobic 1,1-dimethylallyl substituent at position C-8. brucei rhodesience. Similarly, T. procumbens showed Brandio et al. [13] first reported the antimalarial significant antileishmanial activity against promastigotes activity of crude extracts and their fractions from different of Leishmania mexicana. The active principle was found to species of Bidens, and provided evidence that this is due to be an oxylipin, namely (3S)-16, 17- didehydrofalcarinol [76]. the presence of polyacetylene and flavonoids. Later, Kumari et al. [63] and Tobinaga et al. [151] isolated the polyacetylene compound (R)-1,2-dihydroxytrideca- Antiparasitic activity of flavonoids and 3,5,7,9,11-pentayne from leaf extracts of B. pilosa, which terpenoids documented in Asteraceae showed promising antimalarial activity against Plasmo- dium falciparum (Table 3). Moreover, this compound was Flavonoids are the class of compound of highest tested in an in vivo model (mice infected with Plasmodium occurrence, wide structural diversity, and chemical berghei NK-65 strain), and results showed that the stability. They have been isolated on a large scale from compound can decrease the average parasitaemia in red Asteraceae species and can be used as taxonomic markers blood cells, but further studies addressing its mechanism at lower hierarchical levels [75]. Flavones and flavonols are required. The genus Calendula is very well studied for are common throughout the Asteraceae, i.e., glycosides its phytochemistry, with triterpene alcohols, triterpene of apigenin, luteolin, kaempferol, quercetin, flavanone saponins, flavonoids, carotenoids and polysaccharides as derivatives, ()-epicatechin and ()-epigallocatechin the major classes of phytoconstituents. Szakie et al. [145] (Figure 1). Although there are fewer reports on anti- isolated several oleanolic acid glycoside derivatives and giardial activity in Asteraceae, these compounds from tested them against Heligmosomoides polygyrus; the other families are well-studied against G. lamblia. From wormicidal activity of the oleanolic acid glycosides was the aerial parts of Helianthemum glomeratum (Cistaceae), superior to that of the aglycone, and the level of activity kaempferol, quercetin, ()-epicatechin and ()-epigallo- was dependent on the nature of the sugar side-chain at the catechin have shown antigiardial activity against fi C-3 position. The rst sugar molecule of the glucuronides, G. lamblia (in vitro), with IC50 values of 26.47, 8.73, i.e., the glucuronic acid attached to the aglycone, 1.64 and 8.06 mg/mL, respectively [17]. Structure-activity appeared to be vital for the antiparasitic properties of correlation implies that the 2,3-double bond and 4-keto these compounds [145]. E. prostrata was studied by several group of flavones might not be required for antiprotozoal scientists for its antiparasitic properties such as antima- activity since both ()-epicatechin and ()-epigalloca- larial [6], antileishmanial [56,138], and anthelmintic techin lack these structural units, yet maintain biological activities [11,50]. Khanna et al. [56] isolated dasyscyphin activity (Figure 1). Also, unlike flavones, the benzenediol C from the leaves and proved its antileishmanial activities moiety of ()-epicatechin and () epigallocatechin is not against Leishmania major, Leishmania aethiopica and coplanar with the heterocyclic part because C-2 of their S.K. Panda and W. Luyten: Parasite 2018, 25,10 11

Table 3. List of compounds from Asteraceae commonly reported for their antiparasitic properties.

Plant1 Name of the compounds/group Organism tested References Acanthospermum hispidum DC. Sesquiterpenic lactones Plasmodium falciparum [34]

Acmella ciliate (Kunth) Cass. Spilanthol Trypanosoma brucei rhodesiense and [137] Plasmodium falciparum

Ageratum conyzoides (L.) L. Methoxylated flavonoids Trypanosoma brucei rhodesiense, [98] Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum Ambrosia tenuifolia Spreng. Psilostachyin Leishmania mexicana [143] Peruvin

Ambrosia tenuifolia Spreng. and Psilostachyin and psilostachyin C Trypanosoma cruzi [143] Ambrosia scabra Hook. & Arn.

Artemisia annua L. Sesquiterpenes and sesquiterpene Plasmodium falciparum [127] lactones

Aspilia africana (Pers.) C. D. Thiarubrine A Caenorhabditis elegans [128] Adams

Baccharis retusa DC. Sakuranetin Leishmania sp. [40]

Baccharis uncinella DC. Caffeic acid Leishmania amazonensis [116] Pectolinarigenin Leishmania braziliensis

Bidens pilosa L. Polyacetylene Plasmodium falciparum [63,151]

Bidens sulphurea (Cav.) Sch. 2,6-Di-tert-butyl-4-methylphenol, Schistosoma mansoni [1] Bip. germacrene D, b-caryophyllene

Calendula officinalis L. Glycosides of oleanolic acid Heligmosomoides polygyrus [145]

Centipeda minima (L.) Sesquiterpene lactone, brevilin A Giardia intestinalis [164] A. Braun & Asch. Entamoeba histolytica Plasmodium falciparum

Chromolaena odorata f. odorata Quercetin-4’-methyl ether Plasmodium falciparum [23]

Cichorium intybus L. Sesquiterpene lactone Haemonchus contortus [26]

Coreopsis lanceolate L. 1-Phenylhepta-1,3,5-triyne and 5- Bursaphelenchus xylophilus and [55] phenyl-2-(1’-propynyl)-thiophene Caenorhabditis elegans

Dicoma tomentosa Cass. Sesquiterpene lactones Plasmodium falciparum [48] 3D7 and W2

Dicoma anomala subsp. gerrardii Eudesmanolide-type sesquiterpene Plasmodium falciparum D10 [38] (Harv. ex F. C. Wilson) S. Ortiz lactone & Rodr. Oubiña

Eclipta prostrata (L.) L. Dasyscyphin C Leishmania major, [56] Leishmania aethiopica, Leishmania tropica 12 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 3. (continued).

Plant1 Name of the compounds/group Organism tested References Elephantopus scaber L. Deoxyelephantopin Trypanosoma brucei rhodesience, [165] strain STIB 900

Fructus arctii Arctigenin and arctiin Dactylogyrus intermedius [158]

Heterotheca inuloides Cass. 7-Hydroxy-3,4-dihydrocadalene, Giardia intestinalis [129] 7-hydroxycalamenene

Kleinia odora (Forssk.) DC. Ursolic acid and derivatives Plasmodium falciparum [89] Leishmania infantum Trypanosoma cruzi Trypanosoma brucei

Pentacalia desiderabilis Cuatrec. Jacaranone Leishmania braziliensis [83] Leishmania amazonensis

Porophyllum ruderale (Jacq.) Thiophene derivatives Leishmania amazonensis [146] Cass.

Sphaeranthus indicus L. Indicusalactone, ()-oxyfrullanolide, Plasmodium falciparum [132] 7-Hydroxyfrullanolide, squalene, 3,5-di-O-caffeoylquinic acid methyl ester, 3,4-di-O-caffeoylquinic acid methyl ester

Tagetes erecta L. 2-Hydroxymethyl-non-3-ynoic acid, Plasmodium falciparum MRC-pf-2 [41] 2-[2,2’]-bithiophenyl-5- ethyl ester Plasmodium falciparum MRC-pf-56

Tagetes patula L. Synonym of a-terthienyl, gallic and linoleic acids Heterodera zeae [24] Tagetes erecta L.

Tridax procumbens (L.) L. (3s)-16,17-Didehydrofalcarinol, Leishmania mexicana [75] (3S)-16,17-didehydrofalcarinol Leishmania mexicana [75] Tanacetum parthenium (L.) Sch. Parthenolide Leishmania amazonensis [150] Bip.

Tithonia diversifolia (Hemsl.) A. Sesquiterpenes and sesquiterpene Plasmodium falciparum [38] Gray lactones

Trixis antimenorrhoea (Schrank) Trixanolide Leishmania amazonensis [72] Mart. ex Baker Leishmania braziliensis

Vernonia amygdalina Delile Sesquiterpenes and sesquiterpene Plasmodium falciparum [100] lactones

Vernonia brachycalyx O. Hoffm. Sesquiterpene dilactone Plasmodium falciparum (K39, 3D7, [101] V1/S and Dd2)

Vernonia angulifolia DC. Sesquiterpenes and sesquiterpene Plasmodium falciparum [121] lactones

Xanthium macrocarpum DC. Xanthanolides (xanthinosin Leishmania mexicana [65] xanthatin, xanthinin, 4-epiisoxanthanol, Leishmania infantum 4-epixanthanol) 1 All taxonomic names were verified in the Global Composite Checklist database (http://compositae.landcareresearch.co.nz/Default.aspx) S.K. Panda and W. Luyten: Parasite 2018, 25,10 13

Figure 1. Common flavonoids of the Asteraceae family reported as antiparasitic compounds

flavan-3-ol structure is an sp3 carbon. In addition, there showed IC50 values of 11 ± 1 mM and 12 ± 1 mM for strains are several reports that glycosylated flavonoids also 3D7 and 7G8, respectively. Although luteolin was found to possess antigiardial activity. Also, a C-3 glycosylated prevent the progression of parasite growth beyond the flavone tiliroside [17,79], obtained from H. glomeratum, young trophozoite stage, it did not affect parasite has been shown to possess antigiardial inhibitory activity susceptibility to the antimalarial drugs chloroquine or with an IC50 value of 17.36 mg/mL. artemisinin. Nour et al.,[98] found moderate antiparasitic Recently, Klongsiriwet et al. [57] demonstrated that activity of five methoxylated flavonoids viz. 5,6,7,8,5- quercetin and luteolin are highly effective at 250 mMto pentamethoxy-3,4-methylenedioxyflavone (eupalestin), reduce the in vitro exsheathment of Haemonchus con- 5,6,7,5-tetramethoxy-3,4-methylenedioxyflavone; 5,6,7,8, tortus L3 larvae. Tasdemir et al. studied the antitrypa- 3,4,5-heptamethoxy-flavone (5-methoxynobiletine), 5,6, nosomal and antileishmanial activities of flavonoids and 7,3,4,5-hexamethoxy-flavone and 4-hydroxy-5,6,7,3,5-pen- their analogues in vitro and in vivo, as well as their tamethoxy-flavone (ageconyflavone) against several para- (quantitative) structure-activity relationship [148]. They sites: Trypanosoma brucei rhodesiense, Trypanosoma showed that fisetin, 3-hydroxyflavone, luteolin, and cruzi, Leishmania donovani and Plasmodium falciparum quercetin are the most potent antileishmanial compounds (Table 4). against Leishmania donovani, with IC50 of 0.6, 0.7, 0.8, Terpenoids are the largest group of phytochemicals as and 1.0 mg/mL, respectively (Table 4). Moreover, these they comprise more than 20,000 recognised molecules. authors found moderate antitrypanosomal efficacy of Depending on the number of carbons, terpenoids are these compounds against Trypanosoma brucei rhode- divided into classes, starting with sesquiterpenes and siense and Trypanosoma cruzi. The authors conclude that continuing with diterpenes, sterols, triterpenes and finally 7,8-dihydroxyflavone and quercetin appeared to amelio- tetraterpenes. Several sesquiterpenes, sterols and triter- rate parasitic infections in mouse models, and are potent penes have been isolated from members of the Asteraceae and effective antiprotozoal agents. Mead and McNair [78] family. The sesquiterpenes commonly found in leaf also studied the antiparasitic activity of flavonoids and extracts from Asteraceae are divided into mono- and isoflavones against Cryptosporidium parvum and Ence- bicyclic. The most abundant sterols from Asteraceae are phalitozoon intestinalis. These authors also found that stigmasterol and sitosterol. Sequiterpenes isolated from quercetin and apigenin had activity against Encephalito- Vernonia spp. have antiparasitic activity against Plasmo- zoon intestinalis at EC50 of 15 and 50 mM, respectively, dium falciparum. Four compounds such as vernodalin, while low activity of luteolin and quercetin was found vernodalol, vernolide, and hydroxyvernolide (Figure 2), against Cryptosporidium parvum. No inhibition was all derived from the leaves of Vernonia amygdalina, have observed with either rutin or epigallocatechin gallate potent activity with IC50 values of 4, 4.2, 8.4 and 11.4 mg/ against either parasite. Lehane and Saliba [66] investigat- mL, respectively [60]. Another compound: sesquiterpene ed the effects of a range of common dietary flavonoids on dilactone (16,17-dihydrobrachycalyxolide), isolated from the growth of two strains of the human malaria parasite the leaves of V. brachycalyx, exhibited anti-plasmodial Plasmodium falciparum and concluded that luteolin activity against different multidrug-resistant strains of 14 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 4. Selected flavonoids and terpenoids (whose presence has been reported in plants of the Asteraceae family) with antiparasitic activity

Flavonoids Organism tested Concentration/ References dose IC50 Four polyoxygenated flavonoids Trypanosoma brucei rhodesiense C1: 16 mM, C2: 18 mM, [97] C3: 21 mM and C4: 11 mM

5,6,7,8,5-Pentamethoxy-3,4-methylenedioxy Trypanosoma brucei rhodesiense; Tb: 6.67 mg/mL [98] flavone Trypanosoma cruzi; Tc- > 30 mg/mL Leishmania donovani and Ld: > 30 mg/mL Plasmodium falciparum Pf: 4.57 mg/mL

5,6,7,5-Tetramethoxy-3,4-methylenedioxyflavone Trypanosoma brucei rhodesiense; Tb: 7.29 mg/mL [98] Trypanosoma cruzi; Tc: 19.5 mg/mL Leishmania donovani and Ld: > 30 mg/mL Plasmodium falciparum Pf: 4.26 mg/mL

5,6,7,8,3,4,5-Hepta-methoxyflavone Trypanosoma brucei rhodesiense; Tb: 4.76 mg/mL [98] Trypanosoma cruzi; Tc; 26.4 mg/mL Leishmania donovani and Ld: 5.29 mg/mL Plasmodium falciparum Pf: > 5 mg/mL

5,6,7,3,4,5-Hexamethoxyflavone Trypanosoma brucei rhodesiense; Tb: 8.58 mg/mL [98] Trypanosoma cruzi; Tc: > 30 mg/mL Leishmania donovani and Ld: 8.61 mg/mL Plasmodium falciparum Pf: 2.99 mg/mL

4-Hydroxy-5,6,7,3,5-pentamethoxyflavone Trypanosoma brucei rhodesiense; Tb: 3.01 mg/mL [98] (ageconyflavone C) Trypanosoma cruzi; Tc: > 30 mg/mL Leishmania donovani and Ld: 3.56 mg/mL Plasmodium falciparum Pf: 3.59 mg/mL

3, 5, 7, 3’-Tetrahydroxy-4’-methoxyflavone Plasmodium falciparum – [23]

Bractein Leishmania donovani – [54]

Kaempferol Giardia lamblia 26.47 mg/mL [17]

Quercetin Giardia lamblia 8.73 mg/mL [17]

()-Epicatechin Giardia lamblia 1.64 mg/mL [17]

()-Epigallocatechin Giardia lamblia 8.06 mg/mL [17] Quercetin Haemonchus contortus 250 mg/mL as highest [57] concentration

Luteolin Haemonchus contortus 250 mg/mL as highest [57] concentration Leishmania donovani 0.8 mg/mL [148]

Quercetin Leishmania donovani 1 mg/mL [148]

Fisetin Leishmania donovani 0.6 mg/mL [148] S.K. Panda and W. Luyten: Parasite 2018, 25,10 15

Table 4. (continued).

Flavonoids Organism tested Concentration/ References dose IC50 3-Hydroxyflavone Leishmania donovani 0.7 mg/mL [148]

Luteolin Plasmodium falciparum 3D7 and 7G8 3D7: 11 mg/mL [66] 7G8: 12 mg/mL

Terpenoids

Vernodalin Plasmodium falciparum 4 mg/mL [100]

Vernodalol Plasmodium falciparum 4.2 mg/mL [100]

Vernolide Plasmodium falciparum 8.4 mg/mL [100]

Hydroxyvernolide Plasmodium falciparum 11.4 mg/mL [100]

16,17- Dihydrobrachycalyxolide Plasmodium falciparum (K39, 3D7, K39: 4.2 mg/mL [101] V1/S and Dd2) 3D7: 13.7 mg/mL V1/S: 3 mg/mL Dd2: 16 mg/mL

Tagitinin C Plasmodium falciparum 0.75 mg/mL [38]

15-Acetoxy-8 b-[(2-methylbutyryloxy)]-14-oxo-4, Plasmodium falciparum 3D7 2.9 mg/mL [34] 5-cis-acanthospermolide)

9 a-Acetoxy-15-hydroxy- 8 b-(2- Plasmodium falciparum 3D7 2.23 mg/mL [34] methylbutyryloxy)-14-oxo- 4,5-Trans- acanthospermolide

3 b-Hydroxyolean-12-en-28-oic acid (oleanolic Leishmania amazonensis La: > 100 mg/mL [116,162], acid) [161] Leishmania braziliensis –

3 b-Hydroxyurs-12-en-28-oic acid (ursolic acid) Leishmania infantum Li: 7.4 mM[89] Trypanosoma brucei Tb: 2.2 mM Trypanosoma cruzi Tc: 8.8 mM Plasmodium falciparum Pf: 29.7 mM

Indicusalactone Plasmodium falciparum 2.8 mg/mL [132]

()-Oxyfrullanolide Plasmodium falciparum 3.8 mg/mL [132]

7-Hydroxyfrullanolide, Plasmodium falciparum 2.5 mg/mL [132]

Squalene Plasmodium falciparum 2.3 mg/mL [132]

3,5-Di-O-caffeoylquinic acid methyl ester Plasmodium falciparum 2.4 mg/mL [132]

(3s)-16,17-Didehydrofalcarinol Leishmania mexicana 0.48 mM[76] 16 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Table 4. (continued).

Flavonoids Organism tested Concentration/ References dose IC50 Ursolic acid Leishmania amazonensis 6.4 mg/mL [162] Leishmania infantum In vivo 1.0 mg/kg body [49] weight (mice)

Urs-12-ene-3 b,16 b-diol Plasmodium falciparum Pf: 9.7 mM[89] Leishmania infantum Li: 9.3 mM Trypanosoma cruzi Tc: 9.9 mM Trypanosoma brucei Tb: 2.3 mM

3 b,11a-Dihydroxyurs-12-ene Plasmodium falciparum Pf: 23.9 mM[89] Leishmania infantum Li: 3.2 mM Trypanosoma cruzi Tc: 8.1 mM Trypanosoma brucei Tb: 7.8 mM

Betulinic acid Caenorhabditis elegans 100 mg/mL [22] Plasmodium falciparum W2 2.33 mg/mL [91] b-Sitosterol Trypanosoma brucei brucei S427 12.5 mg/mL [99]

Figure 2. Common terpenoids of the Asteraceae family reported as antiparasitic compounds

Plasmodium falciparum (K39, 3D7, V1/S and Dd2) with the antiplasmodial activity against Plasmodium falcipa- IC50 values of 4.2, 13.7, 3.0, and 16 mg/mL, respectively rum 3D7 and W2 strains. Ganfon et al. [34] investigated [101]. Goffin et al. [38] isolated the sesquiterpene lactone: the antiparasitic activities of Acanthospermum hispidum tagitinin C, from the ether extract of Tithonia diversifolia by isolating two sesquiterpene lactones (15-acetoxy-8 b- and demonstrated antiplasmodial activity against Plas- [(2-methylbutyryloxy)]-14-oxo-4,5-cis-acanthospermo- modium falciparum (IC50 of 0.75 mg/mL). Becker et al. [8] lide), and 9 a-acetoxy-15-hydroxy-8b-(2-methylbutyry- identified urospermal A-15-O-acetate and dehydrobra- 499 loxy)-14-oxo-4,5-transacanthospermolide), both of chylaenolide as the main active compound responsible for which exhibited in vitro antiplasmodial activity against S.K. Panda and W. Luyten: Parasite 2018, 25,10 17

a chloroquine-sensitive strain (3D7) with IC50 values of 2.9 artemether, artemisinin, artesunate, coarsucam, co-arte- and 2.23 mM, respectively (Table 4). mether, dihydroartemisinin and santonin (all from Among the triterpenes, squalene and lupeol deriva- Artemisia species). Also, there are a few drugs still in tives are the more common ones [67]. Oleanolic acid (3 b- clinical trials as antiparasitics, such as artemisone, hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpe- arterolane and artelinic acid [92]. noid with widespread occurrence in Asteraceae and was Traditional knowledge has proven a useful tool in the found to have antimalarial and antileishmanial activity search for new plant-based medicines [18]. It has been [89,162]. Recently, Yamamoto et al. [162] studied the estimated that the number of traditionally used plant activity of ursolic acid on Leishmania amazonensis (in species worldwide is between 10,000 and 53,000 [77]. In vitro and in vivo). They found that ursolic acid eliminated India alone, there are about 25,000 plant-based formula- Leishmania amazonensis promastigotes with an EC50 of tions used in folk and traditional medicine [126]. However, 6.4 mg/mL, comparable with miltefosine, while oleanolic only a small proportion have been screened for biological acid presented only a marginal effect on promastigote activity [42,140]. Also, there are many specific regions that forms at 100 mg/mL. The possible mechanism by which are less studied than others (only 1% of tropical floras have promastigotes were eliminated by ursolic acid was been investigated) [42]. Odisha’s unique location in programmed cell death, independent of caspase 3/7, but Peninsular India has blessed it with an interesting it was highly dependent on mitochondrial activity. Also, assemblage of floral and faunal diversity (http://odi the ursolic acid was not toxic for peritoneal macrophages shasbb.nic.in/index.php?lang=en). The state is on the from BALB/c mice, and it could eliminate intracellular eastern seaboard of India, located between 17° 49’ and 22° amastigotes, associated with nitric oxide (NO) produc- 36’ N latitudes and between 81° 36’ and 8°718’ E tion. These authors conclude that ursolic acid can be longitudes. It covers an area of 1,55,707 sq km and is considered an interesting candidate for future testing as a broadly divided into four geographical regions, i.e. the prototype drug for the treatment of cutaneous leishmani- Northern Plateau (Chhotanagpur), Central River Basins, asis. Enwerem et al. [22] examined the anthelmintic Eastern Hills and Coastal Plains. The confluence of two activity of betulinic acid on C. elegans and confirmed its major biogeographic provinces of India: the Eastern Ghats strong anthelmintic activity at 100 mg/mL, comparable to (South-West) and Chhotanagpur Plateau (North), make piperazine. Bringmann et al. [14] observed that betulinic Odisha a rich biodiversity repository with two interna- acid exhibited moderate to good in vitro antimalarial tionally well-recognised areas: the Similipal Biosphere activity against asexual erythrocytic stages of Plasmodi- Reserve and the Chilika Lagoon. The state has a um falciparum. Later, Steele et al. [141] concluded that biodiversity board (it is a statutory body established betulinic acid can inhibit Plasmodium falciparum (in under the Biological Diversity Act of 2002), with a vitro), while in vivo experiments failed to reduce para- network of 19 wildlife sanctuaries, one national park, one sitaemia (up to 500 mg/mL in a murine malaria model- proposed national park, one biosphere reserve, two tiger mice infected with P. berghei) and exhibited some toxicity. reserves and three elephant reserves (http://odishasbb. However, Ndjakou Lenta et al. [91] isolated betulinic acid, nic.in/index.php?lang=en). Throughout the state, one studied its in vitro activity against the Plasmodium finds varied and widespread forests harbouring different falciparum W2 strain, and found it to be very potent with types of vegetation such as semi-evergreen forests, tropical an IC50 of 2.33 mg/mL. Nweze et al. [99] observed that moist deciduous forests, tropical dry-deciduous forests b-sitosterol has modest anti-trypanosomal activity against and littoral and tidal swamp forests, as well as mangroves Trypanosoma brucei S427 (in vitro IC50 12.5 mg/mL). with unique, endemic, rare and endangered floral and faunal species. The climate of Odisha is characterised by Discussion tropical monsoon weather as its coast borders the Bay of Bengal. The weather is classified as summer, monsoon and In a review on nature-derived drugs, Zhu et al. [166] winter. Searing hot summers with considerably high analysed “the ranking of drug-productive plant families monsoon downpours and cool, pleasant winters mark based on the ratio of the approved drugs to reported the Odisha climate. The average rainfall varies from bioactive natural products (including leads of the 1200 mm to 1700 mm across the state, and is the main approved and clinical trials drugs)” and concluded that source of water. Moreover, the state is vulnerable to there are a few top-ranked plant families that produce high multiple disasters such as tropical cyclones, storm surges numbers of approved drugs among plant-derived medi- and tsunamis due to its sub-tropical littoral location cines. According to Zhu et al. [166], Asteraceae is the (http://nidm.gov.in/default.asp). About 62 ethnic tribal fourth-largest drug-productive family that has yielded communities have been reported in Odisha, of which 13 are many approved drugs, including antiparasitic, anticancer, known as "Particularly Vulnerable Tribal Groups" antiglaucoma, ant-inflammatory, antihepatotoxic, antivi- (https://en.wikipedia.org/wiki/List_of_Scheduled_Tri ral and choleretic agents. From 7229 Asteraceae species, bes_in_Odisha). Districts such as Kandhamala, Kora- 25 clinical drugs (17 approved and 8 in clinical trials) were put, Malkanigiri, Mayurbhanj, Nabrangpur, Rayagada documented among 1016 searchable drugs [91,99]. There and Sundargarh have scheduled tribes (officially desig- are many FDA-approved nature-derived drugs that nated groups of historically disadvantaged people in originate from Asteraceae as antiparasitics: arteether, India) above 50% of the total population. The social, 18 S.K. Panda and W. Luyten: Parasite 2018, 25,10 cultural and religious life of aboriginal people is influenced proved the anthelmintic properties of Vernonia anthel- by nature and natural resources available in and around mintica against Haemonchus contortus [103,106,140]. their habitat, which provides their food, medicine, shelter, Further study is needed to determine the active anthel- and various other materials and cultural needs [109,110]. mintic compounds. The tribes of Odisha frequently use Sasil-Lagoudakis et al. [133] published a review two other species of Vernonia: V. albicans and V. cinerea. entitled “phylogenies reveal the predictive power of These plants are also interesting for future study to traditional medicine in bioprospecting”. Their study, discover active molecules with antiparasitic properties. which includes the Asteraceae family, provides unique The antitrypanosomal activity of a crude 50% ethanol large-scale evidence that plant bioactivity underlies extract of Xanthium strumarium leaves was studied in traditional medicine. According to these authors, “related vitro and in vivo. The extract exhibited trypanocidal plants are traditionally used as medicines in different activity against Trypanosoma evansi-infected mice [147]. regions, and these plant groups coincide with groups that The authors hypothesised that the presence of xanthinin are used to produce pharmaceutical drugs”. The authors may be responsible for its trypanocidal activity, but conclude that “phylogenetic cross-cultural comparisons further study is needed to definitively identify the can focus screening efforts on a subset of traditionally antitrypanosomal compound or compounds. used plants that are richer in bioactive compounds, and could revitalise the use of traditional knowledge in Conclusion bioprospecting”. Gertrude et al. [36] studied the anthelmintic activity of A search for new antiparasitic drugs has been Bidens pilosa leaf against Haemonchus contortus eggs and under way over the past several decades. However, larvae and concluded that ethanolic extracts have the despite the abundant literature, more work is needed to potential to inhibit the growth of Haemonchus contortus. yield potent, commercially available drugs based on However, further study on the isolation of the active natural products. Fortunately, academic drug discovery compounds as well as in vivo studies are needed. Similarly, for neglected diseases has intensified (e.g. the Drugs for antileishmanial activity of Bidens pilosa leaf was reported Neglected Disease Initiative http://www.dndi.org/), by several researchers [31,85], but no compound responsi- and this includes efforts to use natural products (e.g. ble for this activity has been identified so far. The Research Network Natural Products against Neglected anthelmintic and wormicidal properties of Blumea lacera Diseases https://www.facebook.com/ResNetNPND/ leaf were evaluated against Ascaris lumbricoides and app/435433039823956). Although many Asteraceae Pheretima posthuma [119], but no bioactive compounds species were already studied for different antiparasitic have been acknowledged so far. Calendula officinalis has activities, some of the species important in traditional been used traditionally by the tribes of Odisha for worm medicines have still hardly been studied for their infections. Nikmehr et al. [95] found that crude methanolic bioactivity. Therefore, the present review aims to extracts have antileishmanial activity, but no bioactive encourage further exploration of their potential bioac- molecules have been isolated so far. Caesulia axillaris,a tivity and particularly their antiparasitic properties, wetland plant, is used very frequently for the treatment of guided by the knowledge on the use of Asteraceae malaria by the coastal peoples of Odisha. However, despite plants by the tribes of Odisha and corresponding its long traditional use, its scientific validation as an traditional uses elsewhere in the world. The work antiparasitic agent has not been established so far. Also, reported here highlights the traditional uses of Aster- the phytochemistry of this plant is not well known, except aceae plants of Odisha for the treatment of parasites. for a few studies on its essential oils. Similarly, plants such Plants such as Bidens pilosa, Blumea lacera, Caesulia as Centipeda minima, Sphaeranthus indicus and Tagetes axillaris, Centipeda minima and Sphaeranthus indicus erecta are used as anthelmintic plants by the tribes of deserve to be studied further, especially concerning their Odisha for the treatment of worm infections. Yu et al. [164] most relevant bioactive properties and significant found antiparasitic activity of crude extracts of Centipeda bioactive compounds that could be purified with state- minima and its fractions against Giardia intestinalis, of-the-art methods. Entamoeba histolytica and Plasmodium falciparum. Crude extracts of Sphaeranthus indicus also showed Acknowledgment. The authors are thankful to KU Leuven for antiparasitic effects on Ascaridia galli, Entamoeba histo- providing the necessary facilities during preparation of this lytica and Setaria digitate [96,134]. Organic and aqueous review article. This project received funding from the European ’ extracts of Tagetes erecta show antiparasitic [41], and Union s Horizon 2020 research and innovation programme under fl anthelmintic properties [106]. However, notwithstanding Grant agreement No 633589. This publication re ects only the authors’ views and the Commission is not responsible for any use phytochemical studies, no anti-parasitic compounds have that may be made of the information it contains. been identified, nor have any in vivo studies been conducted so far on these plants. The plant Elephantopus scaber showed anthelmintic activity against Pheretima Conflict of interest posthuma in crude extract. However, further study is required to find out the active anthelmintic compounds. The authors declare that they have no conflict of Both in vitro and in vivo studies were carried out and interest. S.K. Panda and W. Luyten: Parasite 2018, 25,10 19

References Isolation from Triphyophyllum peltatum and Ancistrocla- dus heyneanus, antimalarial activity, and crystal struc- 1. Aguiar GP, Melo NI, Wakabayashi KAL, Lopes MHS, ture of the benzyl ester. Planta Medica, 63, 255–257. Mantovani ALL, Dias HJ, Fukui MJ, Keles LC, Rodrigues 15. Brun R, Don R, Jacobs RT, Wang MZ, Barrett MP. 2011. V, Groppo M, Silva-Filho AA, Cunha WR, Magalhães LG, Development of novel drugs for human African trypano- Crotti AEM. 2013. Chemical composition and in vitro somiasis. Future Microbiology, 6, 677–691. schistosomicidal activity of the essential oil from the 16. Byng JW. The flowering plants handbook: a practical flowers of Bidens sulphurea (Asteraceae). Natural Prod- guide to families and genera of the world. Plant Gateway uct Research, 27, 920–924. Ltd., Hertford, Plant Gateway Ltd., 2004. 2. Akendengué B. 1992. Medicinal plants used by the Fang 17. Calzada F, Meckes M, Cedillo-Rivera R. 1999. Anti- traditional healers in Equatorial Guinea. Journal of amoebic and antigiardial activity of plant flavonoids. Ethnopharmacology, 37, 165–173. Planta Medica, 65, 78–80. 3. Alvarenga SA, Ferreira MJ, Emerenciano V, Cabrol-Bass 18. Cox PA. 2000. Will tribal knowledge survive the D. 2001. Chemosystematic studies of natural compounds millennium? Science, 287, 44–45. isolated from Asteraceae: characterization of tribes by 19. Das M, Mukherjee A. 2014. Elephantopus scaber L.: An principal component analysis. Chemometrics and Intelli- overview. Indian Journal Life Science, 4, 51–54. gent Laboratory Systems, 56, 27–37. 20. de Almeida LMS, Carvalho LSA de, Gazolla MC, Silva 4. Ashok P, Koti BC, Thippeswamy AHM, Tikare VP, Pinto PL, Silva MPN da, de Moraes J, Da Silva Filho AA. Dabadi P, Viswanathaswamy AHM. 2010. Evaluation of 2016. Flavonoids and sesquiterpene lactones from Arte- antiinflammatory activity of Centratherum anthelminti- misia absinthium and Tanacetum parthenium against cum (L) Kuntze Seed. Indian Journal of Pharmaceutical Schistosoma mansoni worms. Evidence-Based Comple- Sciences, 72, 697–703. mentary and Alternative Medicine, 9521349. 5. Bailen M, Julio LF, Diaz CE, Sanz J, Martínez-Díaz RA, 21. Elford BC, Roberts MF, Phillipson JD, Wilson RJM. Cabrera R, Burillo J, Gonzalez-Coloma A. 2013. Chemical 1987. Potentiation of the antimalarial activity of qing- composition and biological effects of essential oils from haosu by methoxylated flavones. Transactions of the Artemisia absinthium L. cultivated under different Royal Society of Tropical Medicine and Hygiene, 81, 434– environmental conditions. Industrial Crops and Products, 436. 49, 102–107. 22. Enwerem NM, Okogun JI, Wambebe CO, Okorie DA, 6. Bapna S, Adsule S, Shirshat Mahendra S, Jadhav S, Patil Akah PA. 2001. Anthelmintic activity of the stem bark LS, Deshmukh RA. 2007. Anti–malarial activity of Eclipta extracts of Berlina grandiflora and one of its active alba against Plasmodium berghei infection in mice. principles, Betulinic acid. Phytomedicine, 8, 112–114. Journal of Communicable Diseases, 39, 91–104. 23. Ezenyi IC, Salawu OA, Kulkarni R, Emeje M. 2014. 7. Bartolome AP, Villaseñor IM, Yang W-C., Yang W-C. Antiplasmodial activity-aided isolation and identification 2013. Bidens pilosa L. (Asteraceae): Botanical properties, of quercetin-4’-methyl ether in Chromolaena odorata leaf traditional uses, phytochemistry, and pharmacology. fraction with high activity against chloroquine-resistant Evidence-based Complementary and Alternative Medi- Plasmodium falciparum. Parasitology Research, 113, cine, 340215. 4415–4422. 8. Becker JV, van der Merwe MM, van Brummelen AC, 24. Faizi S, Fayyaz S, Bano S, Yawar Iqbal E, Siddiqi H, Naz Pillay P, Crampton BG, Mmutlane EM, Parkinson C, van A, Naz A. 2011. Isolation of nematicidal compounds from Heerden FR, Crouch NR, Smith PJ, Mancama DT, Tagetes patula L. yellow flowers: Structure–activity Maharaj VJ. 2011. In vitro anti–plasmodial activity of relationship studies against cyst nematode Heterodera Dicoma anomala subsp. gerrardii (Asteraceae): identifi- zeae infective stage larvae. Journal of Agricultural and cation of its main active constituent, structure–activity Food Chemistry, 59, 9080–9093. relationship studies and gene expression profiling. Malaria 25. Feyera T, Terefe G, Shibeshi W. Evaluation of In vivo Journal, 10, 295. antitrypanosomal activity of crude extracts of Artemisia 9. Berger I, Passreiter CM, Cáceres A, Kubelka W. 2001. abyssinica against a Trypanosoma congolense isolate. Antiprotozoal activity of Neurolaena lobata. Phytother- BMC Complementary and Alternative Medicine, 14, 117. apy Research, 15, 327–330. 26. Foster JG, Cassida KA, Turner KE. 2011. In vitro analysis 10. Bero J, Hannaert V, Chataigné G, Hérent MF, Quetin- of the anthelmintic activity of forage chicory (Cichorium Leclercq J. 2011. In vitro antitrypanosomal and anti- intybus L.) sesquiterpene lactones against a predominantly leishmanial activity of plants used in Benin in traditional Haemonchus contortus egg population. Veterinary Para- medicine and bio-guided fractionation of the most active sitology, 180, 298–306. extract. Journal of Ethnopharmacology, 137, 998–1002. 27. Fournet A, Barrios AA, Muñoz V. 1994. Leishmanicidal 11. Bhinge SD, Hogade MG, Chavan C, Kumbhar M, Chature and trypanocidal activities of Bolivian medicinal plants. V. 2010. In vitro anthelmintic activity of herb extract of Journal of Ethnopharmacology, 41, 19–37. Eclipta prostrate L. against Pheretima posthuma. Asian 28. François G, Passreiter CM, Woerdenbag HJ, Van Journal of Pharma Clinical Research, 3, 229–230. Looveren M. 1996. Antiplasmodial activities and cytotoxic 12. Bisht VK, Purohit V. 2010. Medicinal and aromatic plants effects of aqueous extracts and sesquiterpene lactones from diversity of Asteraceae in Uttarakhand. Nature and Neurolaena lobata. Planta Medica, 62, 126–129. Science, 8, 121–128. 29. Freiburghaus F, Ogwal EN, Nkunya MH, Kaminsky R, 13. Brandão MG, Krettli AU, Soares LS, Nery CG, Marinuzzi Brun R. 1996. In vitro antitrypanosomal activity of HC. 1997. Antimalarial activity of extracts and fractions African plants used in traditional medicine in Uganda to from Bidens pilosa and other Bidens species (Asteraceae) treat sleeping sickness. Tropical Medicine and Interna- correlated with the presence of acetylene and flavonoid tional Health, 1, 765–771. compounds. Journal of Ethnopharmacology, 57, 131–138. 30. Funk VA, Bayer RJ, Keeley S, Chan R, Watson L, 14. Bringmann G, Saeb W, Assi L, François G, Sankara Gemeinholzer B, Schilling E, Panero JL, Baldwin BG, Narayanan A, Peters K, Peters EM. 1997. Betulinic acid: Garcia-Jacas N, Susanna A, Jansen RK. Everywhere but 20 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Antarctica: Using a supertree to understand the diversity against Trichostrongylid nematodes of sheep. Pharma- and distribution of the Compositae. Biologiske Skrifter, ceutical Biology, 44, 563–567. 55, 343–374. 46. Islam MT, Das PR, Kabir MH, Akter S, Khatun Z, Haque 31. Gachet MS, Lecaro JS, Kaiser M, Brun R, Navarrete H, MM, Roney MSI, Jahan R, Rahmatullah M. 2012. Muñoz RA, Bauer R, Schuhly W. 2010. Assessment of Acanthaceae and Asteraceae family plants used by folk anti-protozoal activity of plants traditionally used in medicinal practitioners for treatment of malaria in Ecuador in the treatment of leishmaniasis. Journal of Chittagong and Sylhet divisions of Bangladesh. American- Ethnopharmacology, 128, 184–197. Eurasian Journal of Sustainable Agriculture, 6, 146–152. 32. Gallwitz H, Bonse S, Martinez-Cruz A, Schlichting I, 47. Jahan R, Al-Nahain A, Majumder S, Rahmatullah M. Schumacher K, Krauth-Siegel RL. 1999. Ajoene is an 2014. Ethnopharmacological Significance of Eclipta alba inhibitor and subversive substrate of human glutathione (L.) Hassk. (Asteraceae). International Scholarly Re- reductase and Trypanosoma cruzi trypanothione reduc- search Notices, 385969. tase: Crystallographic, kinetic, and spectroscopic studies. 48. Jansen O, Tits M, Angenot L, Nicolas JP, Patrick De Mol Journal of Medicinal Chemistry, 42, 364–372. JBN, Frédérich M. 2012. Anti–plasmodial activity of 33. Gamboa-Leon R, Vera-Ku M, Peraza-Sanchez SR, Ku- Dicoma tomentosa (Asteraceae) and identification of Chulim C, Horta-Baas A, Rosado-Vallado M. 2014. urospermal A–15–O–acetate as the main active com- Antileishmanial activity of a mixture of Tridax procum- pound. Malaria Journal, 11, 289. bens and Allium sativum in mice. Parasite, 21, 15. 49. Jesus JA, Fragoso TN, Yamamoto ES, Laurenti MD, Silva 34. Ganfon H, Bero J, Tchinda AT, Gbaguidi F, Gbenou J, MS, Ferreira AF, Lago JHG, Gomes GS, Passero LFD. Moudachirou M, Frédérich M, Quetin-Leclercq J. 2012. 2017. Therapeutic effect of ursolic acid in experimental Antiparasitic activities of two sesquiterpenic lactones visceral leishmaniasis. International Journal for Parasi- isolated from Acanthospermum hispidum D.C. Journal of tology: Drugs and Drug Resistance, 7, 1–11. Ethnopharmacology, 141, 411–417. 50. Kamaraj C, Rahuman AA. 2011. Efficacy of anthelmintic 35. García M, Monzote L, Scull R, Herrera P. 2012. Activity of properties of medicinal plant extracts against Haemonchus Cuban plants extracts against Leishmania amazonensis. contortus. Research in Veterinary Science, 91, 400–404. ISRN Pharmacology, 104540. 51. Kamboj A, Saluja AK. 2008. Ageratum conyzoides L.: A 36. Gertrude Mbogning Tayo, Payne VK, Poné JW, Claire review on its phytochemical and pharmacological profile. KM, Jeannette Y, Alidou MN, Mbida M, Bilong CFB. International Journal of Green Pharmacy, 2, 59–68. 2012. In vitro ovicidal and larvicidal activities of aqueous 52. Kamboj A, Saluja AK. 2010. Phytopharmacological and ethanolic extracts of the leaves of Bidens pilosa review of Xanthium strumarium L. (Cocklebur). Interna- (Asteraceae) on Heligmosomoides bakeri (Nematoda: tional Journal of Green Pharmacy, 4, 129–139. Heligmosomatidae). International Journal of Phytomedi- 53. Kantamreddi VSS, Parida S, Kommula SM, Wright CW. cines and Related Industries, 4, 121–125. 2009. Phytotherapy used in Orissa state, India for treating 37. Girach RD, Brahmam M, Misra MK, Ahmed M. 1998. malaria. Phytotherapy Research, 23, 1638–1641. Indigenous phytotherapy for filariasis from Orissa. 54. Kayser O, Kiderlen AF, Folkens U, Kolodziej H. 1999. In Ancient Science of Life, 17, 224–227. vitro leishmanicidal activity of Aurones. Planta Medica, 38. Goffin E, da Cunha AP, Ziemons E, Tits M, Angenot L, 65, 316–319. Frederich M. 2003. Quantification of tagitinin C in 55. Kimura Y, Hiraoka K, Kawano T, Fujioka S, Shimada A. Tithonia diversifolia by reversed-phase high-performance 2017. Nematicidal activities of acetylene compounds from liquid chromatography. Phytochemical Analysis, 14, 378– Coreopsis lanceolata L. Zeitschrift fur Naturforschung 380. C,63, 843–847. 39. Gogate G, Ananthasubramanian L, Nargund KS, Bhat- 56. Khanna VG, Kannabiran K, Getti G. 2009. Leishmani- tacharya SC. 1986. Some interesting sesqueterpenoids cidal activity of saponins isolated from the leaves of from Sphaeranthus indicus Linn. Indian Journal of Eclipta prostrata and Gymnema sylvestre. Indian Journal Chemistry, 25, 233–238. of Pharmacology, 41, 32–35. 40. Grecco SS, Reimão JQ, Tempone AG, Sartorelli P, Cunha 57. Klongsiriwet C, Quijada J, Williams AR, Mueller-Harvey RLOR, Romoff P, Ferreira MJP, Fávero OA, Lago JHG. I, Williamson EM, Hoste H. 2015. Synergistic inhibition of 2012. In vitro antileishmanial and antitrypanosomal Haemonchus contortus exsheathment by flavonoid mono- activities of flavanones from Baccharis retusa DC. mers and condensed tannins. International Journal for (Asteraceae). Experimental Parasitology, 130, 141–145. Parasitology: Drugs and Drug Resistance, 5, 127–134. 41. Gupta P, Vasudeva N. 2010. In vitro antiplasmodial and 58. Koide T, Nose M, Inoue M, Ogihara Y, Yabu Y, Ohta N. antimicrobial potential of Tagetes erecta roots. Pharma- 1998. Trypanocidal effects of gallic acid and related ceutical Biology, 48, 1218–1223. compounds. Planta Medica, 64, 27–30. 42. Gurib-Fakim A. 2006. Medicinal plants: Traditions of 59. Komlaga G, Agyare C, Dickson RA, Mensah MLK, Annan yesterday and drugs of tomorrow. Molecular Aspects of K, Loiseau PM, et al. 2015. Medicinal plants and finished Medicine 27, 1–93. marketed herbal products used in the treatment of malaria 43. Hatimi S, Boudouma M, Bichichi M, Chaib N, Idrissi NG. in the Ashanti region, Ghana. Journal of Ethnopharma- 2001. In vitro evaluation of antileishmania activity of cology,172, 333–436. Artemisia herba alba Asso. Bulletin de la Société de 60. Koshimizu K, Ohigashi H, Huffman MA. Use of Vernonia Pathologie Exotique, 94, 29–31. amygdalina by wild chimpanzee: possible roles of its bitter 44. Hördegen P, Cabaret J, Hertzberg H, Langhans W, and related constituents. Physiology and Behavior, 56, Maurer V. 2006. In vitro screening of six anthelmintic 1209–1216. plant products against larval Haemonchus contortus with 61. Kovendan K, Arivoli S, Maheshwaran R, Baskar K, Vincent a modified methyl-thiazolyl-tetrazolium reduction assay. S. 2012. Larvicidal efficacy of Sphaeranthus indicus, Journal of Ethnopharmacology, 108, 85–89. Cleistanthus collinus and Murraya koenigii leaf extracts 45. Iqbal Z, Lateef M, Jabbar A, Akhtar MS, Khan MN. 2006. against filarial vector, Culex quinquefasciatus Say (Diptera: Anthelmintic activity of Vernonia anthelmintica seeds Culicidae). Parasitology Research, 111, 1025–1035. S.K. Panda and W. Luyten: Parasite 2018, 25,10 21

62. Kuhn T, Wang Y. 2008. Artemisinin-an innovative B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, cornerstone for anti-malaria therapy. Progress in Drug Venketasubramanian N, Vijayakumar L, Vos T, Wagner Research, 66, 385–422. GR, Wang M, Wang W, Watt K, Weinstock MA, 63. Kumari P, Misra K, Sisodia B, Faridi U, Srivastava S, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh P- Luqman S, Darokar M, Negi A, Gupta M, Singh S, Kumar H, Yip P, Zabetian A, Zheng Z-J, Lopez AD, Murray CJ. J. 2009. A promising anticancer and antimalarial compo- 2012. Global and regional mortality from 235 causes of nent from the leaves of Bidens pilosa. Planta Medica, 75, death for 20 age groups in 1990 and 2010: a systematic 59–61. analysis for the global burden of disease study 2010. Lancet, 64. Lans C, Turner N, Khan T, Brauer G. 2007. Ethno- 380, 2095–2128. veterinary medicines used to treat endoparasites and 71. Mahajan NG, Chopda MZ, Mahajan RT. 2015. A review stomach problems in pigs and pets in British Columbia, on Sphaeranthus indicus Linn: Multipotential medicinal Canada. Veterinary Parasitology, 148, 325–340. plant. International Journal of Pharmaceutical Research 65. Lavault M, Landreau A, Larcher G, Bouchara J-P, and Allied Sciences, 4, 48–74. Pagniez F, Le Pape P, Richomme P. 2005. Antileishma- 72. Maldonado EM, Salamanca E, Giménez A, Saavedra G, nial and antifungal activities of xanthanolides isolated Sterner O. 2014. Antileishmanial metabolites from Trixis from Xanthium macrocarpum. Fitoterapia, 76, 363–366. antimenorrhoea. Phytochemistry Letters, 10, 281–286. 66. Lehane AM, Saliba KJ. 2008. Common dietary flavonoids 73. Martín T, Villaescusa L, Gasquet M, Delmas F, inhibit the growth of the intraerythrocytic malaria Bartolomé C, Díaz-Lanza AM, Ollivier E, Balansard parasite. BMC Research Notes, 1, 26. G. 1998. Screening for protozoocidal activity of Spanish 67. Lima Silva F, Fischer DCH, Fechine-Tavares J, Sobral- plants. Pharmaceutical Biology, 36, 56–62. Silva M, Filgueiras de Athayde-Filho P, Barbosa-Filho 74. Martínez-Díaz RA, Ibáñez-Escribano A, Burillo J, De Las JM. 2011. Compilation of secondary metabolites from Heras L, Del Prado G, Agulló-Ortuño MT, Julio LF, Bidens pilosa L. Molecules 16, 1070–1102. González-Coloma A. 2015. Trypanocidal, trichomonaci- 68. Lin YL, Chang CC, Lee IJ. 2008. Review on phytochemi- dal and cytotoxic components of cultivated Artemisia cal study of Asteraceae in Taiwan (1996-2005). Journal of absinthium Linnaeus (Asteraceae) essential oil. Memorias Chinese Medicine, 1934, 135–149. do Instituto Oswaldo Cruz, 110, 693–699. 69. Lockman Y, Vardy D, Ohayon D, el–On J. 1991. The 75. Martín-Quintal Z, Moo-Puc R, González-Salazar F, failure of traditionally used desert plants to act against Chan-Bacab MJ, Torres-Tapia LW, Peraza-Sánchez cutaneous leishmaniasis in experimental animals. Annals SR. 2009. In vitro activity of Tridax procumbens against of Tropical Medicine and Parasitology, 85, 499–501. promastigotes of Leishmania mexicana. Journal of Ethno- 70. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, pharmacology, 122, 463–467. Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, 76. Martio-Quintal Z, del Rosario Garcia-Miss M, Mut- AlMazroa MA, Alvarado M, Anderson HR, Anderson LM, Martin M, Matus-Moo A, Torres-Tapia LW, Peraza- Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Sanchez SR. 2009. The leishmanicidal effect of (3 S)–16, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, 17–didehydrofalcarinol, an oxylipin isolated from Tridax Bikbov B, Abdulhak A Bin, Birbeck G, Blyth F, Bolliger I, procumbens, is independent of NO production. Phyto- Boufous S, Bucello C, Burch M, Burney P, Carapetis J, therapy Research, 24, 1004–1008. Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, 77. McChesney JD, Venkataraman SK, Henri JT. 2007. Plant Colquhoun S, Colson KE, Condon J, Connor MD, Cooper natural products: Back to the future or into extinction? LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Phytochemistry, 68, 2015–2022. Cowie BC, Criqui MH, Cross M, Dabhadkar KC, 78. Mead JR, McNair N. 2006. Antiparasitic activity of Dahodwala N, De Leo D, Degenhardt L, Delossantos A, flavonoids and isoflavones against Cryptosporidium parvum Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey and Encephalitozoon intestinalis. FEMS Microbiology ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Letters, 259, 153–157. Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, 79. Meckes M, Calzada F, Tapia-Contreras A, Cedillo-Rivera Fowkes FGR, Franklin R, Fransen M, Freeman MK, R. 1999. Antiprotozoal properties of Helianthemum Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez- glomeratum. Phytotherapy Research, 13, 102–105. Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller 80. Mishra P, Kumar Mishra S, lacera Pratibha Mishra BD, R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James Irchhiaya R. 2015. Phytochemical investigation and SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, spectral studies of isolated flavonoid from ethanolic Kassebaum N, Keren A, Khoo J-P, Knowlton LM, extract of whole plant. Journal of Pharmacognosy and Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick Phytochemistry, 4, 1–4. M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, 81. Mohanty N, Panda T, Sahoo S, Rath SP. 2015. Herbal folk Mallinger L, March L, Marks GB, Marks R, Matsumori A, remedies of Dhenkanal district, Odisha, India. Interna- Matzopoulos R, Mayosi BM, McAnulty JH, McDermott tional Journal of Herbal Medicine, 3, 24–33. MM, McGrath J, Memish ZA, Mensah GA, Merriman TR, 82. Mokoka T, Zimmermann S, Julianti T, Hata Y, Moodley Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, N, Cal M, Adams M, Kaiser M, Brun R, Koorbanally N, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Hamburger M. 2011. In vitro screening of traditional South Narayan KMV, Nasseri K, Norman P, O’Donnell M, Omer African malaria remedies against Trypanosoma brucei SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian rhodesiense, Trypanosoma cruzi, Leishmania donovani JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, and Plasmodium falciparum. Planta Medica, 77, 1663–1667. Phillips D, Pierce K, Pope CA, Porrini E, Pourmalek F, 83. Morais TR, Romoff P, Fávero OA, Reimão JQ, Lourenço Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, WC, Tempone AG, Hristov AD, Di Santi SM, Lago JHG, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton Sartorelli P, Ferreira MJP. 2012. Anti-malarial, anti- L, Sacco RL, Salomon JA, Sampson U, Sanman E, trypanosomal, and anti-leishmanial activities of jacaranone Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, isolated from Pentacalia desiderabilis (Vell.) Cuatrec. Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas (Asteraceae). Parasitology Research, 110, 95–101. 22 S.K. Panda and W. Luyten: Parasite 2018, 25,10

84. Moshi MJ, Otieno DF, Mbabazi PK, Weisheit A. 2010. 99. Nweze N, Anene B, Asuzu I. 2011. African Journal of Ethnomedicine of the Kagera Region, North Western Biotechnology, 10, 15626–15632. Tanzania. Part 2: The medicinal plants used in Katoro 100. Ohigashi H, Huffman MA, Izutsu D, Koshimizu K, Ward, Bukoba District. Journal of Ethnobiology and Kawanaka M, Sugiyama H, Kirby GC, Warhurst DC, Ethnomedicine, 6, 19. Allen D, Wright CW, David Phillipson J, Timon-David P, 85. Moyo P, Botha ME, Nondaba S, Niemand J, Maharaj VJ, Delmas F, Elias R, Balansard G. 1994. Toward the Eloff JN, Louw AI, Birkholtz L. 2016. In vitro inhibition of chemical ecology of medicinal plant use in chimpanzees: Plasmodium falciparum early and late stage gametocyte The case of Vernonia amygdalina, a plant used by wild viability by extracts from eight traditionally used South chimpanzees possibly for parasite–related diseases. Jour- African plant species. Journal of Ethnopharmacology, nal of Chemical Ecology, 20, 541–553. 185, 235–242. 101. Oketch-Rabah HA, Lemmich E, Dossaji SF, Theander 86. Mujtaba Shah G, Abbasi AM, Khan N, Guo X, Ajab Khan TG, Olsen CE, Cornett IC, Arsalan KV, Christensen SV. M, Hussain M, Bibi S, Nazir A, Ahmad Tahir A. 2014. 1997. Two new antiprotozoal 5-Methylcoumarins from Traditional uses of medicinal plants against malarial Vernonia brachycalyx. Journal of Natural Products, 60, disease by the tribal communities of Lesser Himalayas– 458–461. Pakistan. Journal of Ethnopharmacology, 155, 450–462. 102. Oliveira F, Andrade-Neto V, Krettli A, Brandão MG. 87. Muley B, Khadabadi S, Banarase N. 2009. Phytochemical 2004. New evidences of antimalarial activity of Bidens constituents and pharmacological activities of Calendula pilosa roots extract correlated with polyacetylene and officinalis Linn (Asteraceae): A review. Tropical Journal flavonoids. Journal of Ethnopharmacology, 93, 39–42. of Pharmaceutical Research, 8, 455–465. 103. Olukunle JO, Jacobs EB, Oyewusi JA, Durotoye LA. 88. Murray CJL, Rosenfeld LC, Lim SS, Andrews KG, 2015. Effects of aqueous leaf extract of Tithonia Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano diversifolia (Mexican Sunflower) on semen characteristic R, Lopez AD. 2012. Global malaria mortality between 1980 and morphology in male Wistar albino rats. Nigerian and 2010: a systematic analysis. Lancet, 379, 413–431. Journal of Animal Production, 42, 263–270. 89. Musayeib N, Mothana R, Gamal A, Al-Massarani S, Maes 104. Oryan A, Akbari M. 2016. Worldwide risk factors in L. 2013. In vitro antiprotozoal activity of triterpenoid leishmaniasis. Asian Pacific Journal of Tropical Medicine, constituents of Kleinia Odora growing in Saudi Arabia. 9, 925–932. Molecules, 18, 9207–9218. 105. Oudhia P, Tripathi RS. 1974. A useful weed Blumea lacera 90.MuthauraCN,KerikoJM,MutaiC,YenesewA,Gathirwa L. A review. Indian Journal of Weed Science, 31, 108–109. JW, Irungu BN, Nyangacha R, Mungai GM, Derese S. 2015. 106. Palacios Landín J, Mendoza de Gives P, Salinas Sánchez Antiplasmodial potential of traditional antimalarial phyto- DO, López Arellano ME, Liébano Hernández E, Hernán- therapy remedies used by the Kwale community of the dez Velázquez VM, Valladares Cisneros MG. 2016. In Kenyan Coast. Journal of Ethnopharmacology, 170, 148–157. vitro and in vivo nematocidal activity of Allium sativum 91. Ndjakou Lenta B, Devkota KP, Ngouela S, Fekam Boyom and Tagetes erecta extracts against Haemonchus F, Naz Q, Choudhary MI, Tsamo E, Rosenthal PJ, Sewald contortus. Turkish Journal of Parasitology, 39, 260–264. N. 2008. Anti–plasmodial and cholinesterase inhibiting 107. Panda A, Misra MK. 2011. Ethnomedicinal survey of some activities of some constituents of Psorospermum glaberri- wetland plants of South Orissa and their conservation. mum. Chemical and Pharmaceutical Bulletin, 56, 222–226. Indian Journal of Traditional Knowledge, 10, 296–303. 92. Newman DJ, Cragg GM. 2016. Natural products as 108. Panda SK, Das D, Tripthathy NK. 2015. Phytochemical sources of new drugs from 1981 to 2014. Journal of Natural investigation and anthelmintic activity of various root Products, 79, 629–661. extracts of Gmelina arborea. Asian Journal of Plant 93. Niaz S, Akhtar T, Shams S, AbdEl-Salam NM, Ayaz S, Science and Research, 5, 54–58. Ullah R, Bibi S, Hussain I, Ahmad S. 2015. Treatment of 109. Panda SK, Mohanta YK, Padhi L, Park Y-H., Mohanta bovine schistosomiasis with medicinal plant, Veronia TK, Bae H. 2016. Large scale screening of ethnomedicinal anthelmintica (Kaliziri), an alternative approach. African plants for identification of potential antibacterial com- Journal of Traditional, Complementary and Alternative pounds. Molecules, 21, 293. Medicines, 12S, 78-83. 110. Panda SK, Padhi L, Leyssen P, Liu M, Neyts J, Luyten W. 94. Nibret E, Wink M. 2010. Volatile components of four 2017. Antimicrobial, anthelmintic and antiviral activity of Ethiopian Artemisia species extracts and their In vitro plants traditionally used for treating infectious disease in antitrypanosomal and cytotoxic activities. Phytomedi- the Similipal Biosphere Reserve, Odisha, India. Frontiers cine, 17, 369–374. in Pharmacology, 8, 658. 95. Nikmehr B, Ghaznavi H, Rahbar A, Sadr S, Mehrzadi S. 111. Panda SK, Rout SD, Mishra N, Panda T. 2011. 2014. In vitro anti–leishmanial activity of methanolic Phytotherapy and traditional knowledge of tribal com- extracts of Calendula officinalis flowers, Datura stramo- munities of Mayurbhanj district, Orissa, India. Journal of nium seeds, and Salvia officinalis leaves. Chinese Journal Pharmacognosy and Phytotherapy, 3, 101–113. of Natural Medicines, 12, 423–427. 112. Panda SK. 2014. Ethno-medicinal uses and screening of 96. Nisha M, Kalyanasundaram M, Paily KP, Abidha, plants for antibacterial activity from Similipal Biosphere Vanamail P, Balaraman K. 2006. In vitro screening of Reserve, Odisha, India. Journal of Ethnopharmacology, medicinal plant extracts for macrofilaricidal activity. 151, 158–175. Parasitology Research, 100, 575–579. 113. Pani M, Nahak G, Sahu RK. 2014. Review on ethno- 97. Nour A, Khalid S, Abdallah W, Kaiser M, Brun R, medicinal plants of Odisha for the treatment of malaria. Schmidt T. 2006. Trypanocidal flavonoids from Ageratum International Journal of Pharmacognosy and Phytochem- conyzoides. Planta Medica, 72, P_073. ical Research, 7, 156–165. 98. Nour AMM, Khalid SA, Kaiser M, Brun R, Abdalla WE, 114. Parnham MJ. 1996. Benefit-risk assessment of the Schmidt TJ. 2010. The antiprotozoal activity of methyl- squeezed sap of the purple coneflower (Echinacea ated flavonoids from Ageratum conyzoides L. Journal of purpurea) for long-term oral immunostimulation. Phyto- Ethnopharmacology, 129, 127–130. medicine, 3, 95–102. S.K. Panda and W. Luyten: Parasite 2018, 25,10 23

115. Parveen S, Godara R, Katoch R, Yadav A, Verma PK, 130. Rout SD, Panda SK. 2010. Ethnomedicinal plant Katoch M, Singh NK. 2014. In vitro evaluation of resources of Mayurbhanj district, Orissa. Indian Journal ethanolic extracts of Ageratum conyzoides and Artemisia of Traditional Knowledge, 9, 68–72. absinthium against cattle tick Rhipicephalus microplus. 131. Saini A, Kumar Soni H, Gupta P. 2016. A Review on Scientific World Journal, 858973. Tridax procumbens. Imperial Journal of Interdisciplinary 116. Passero LFD, Bonfim-Melo A, Corbett CEP, Laurenti Research, 2, 308–319. MD, Toyama MH, de Toyama DO, Romoff P, Fávero OA, 132. Sangsopha W, Lekphrom R, Kanokmedhakul S, Kanok- dos Grecco SS, Zalewsky CA, Lago JHG. 2011. Anti- medhakul K. 2016. Cytotoxic and antimalarial constitu- leishmanial effects of purified compounds from aerial parts ents from aerial parts of Sphaeranthus indicus. of Baccharis uncinella C. DC. (Asteraceae). Parasitology Phytochemistry Letters, 17, 278–281. Research, 108, 529–536. 133. Saslis-Lagoudakis CH, Savolainen V, Williamson EM, 117. Pattanaik C, Reddy C, Dhal N. 2008. Phytomedicinal Forest F, Wagstaff SJ, Baral SR, Watson MF, Pendry study of coastal sand dune species of Orissa. Indian CA, Hawkins JA. 2012. Phylogenies reveal predictive Journal of Traditional Knowledge, 7, 263–268. power of traditional medicine in bioprospecting. Pro- 118. Pattanayak B, Dhal NK, Parida S. 2016. Ethnobotanical ceedings of the National Academy of Sciences, 109, survey of antimalarial plants of Odisha, India. Asian 15835–15840. Journal of Science and Technology, 7, 2529–2536. 134. Sharma S, Jalalpure SS, Bhupesh S, Shruti T, Agarwal N. 119. Pattewar AM, Dawalbaje AB, Gundale DM, Pawar PB, 2011. Anthelminitic activity of the whole plant of Kavtikwar PG, Yerawar PP, Pandharkar TM, Patawar Sphaeranthus indius. International Journal of Ayurvedic VA. 2012. Phytochemistry and anthelmintic studies on and Herbal Medicine, 1, 14–21. Blumea lacera. Indo Global Journal of Pharmaceutical 135. Shetty LJ, Sakr FM, Al-Obaidy K, Patel MJ, Shareef H. Sciences, 2, 390–396. 2015. A brief review on medicinal plant Tagetes erecta 120. Pattnaik A, Sarkar R, Sharma A, Yadav KK, Kumar A, Linn A. Journal of Applied Pharmaceutical Science, 5, 91– Roy P, Mazumder A, Karmakar S, Sen T. 2013. 95. Pharmacological studies on Buchanania lanzan Spreng. 136. Shukla AN, Rawat AKS. 2010. An ethnobotanical study of A focus on wound healing with particular reference to anti- medicinal plants of Rewa district, Madhya Pradesh. biofilm properties. Asian Pacific Journal of Tropical Indian Journal of Traditional Knowledge, 9, 191–202. Biomedicine, 3, 967–974. 137. Silveira N, Saar J, Santos A, Barison A, Sandjo L, Kaiser 121. Pedersen MM, Chukwujekwu JC, Lategan CA, Staden J M, Schmidt T, Biavatti M. 2016. A new alkamide with an van, Smith PJ, Staerk D. 2009. Antimalarial sesquiter- endoperoxide structure from Acmella ciliata (Asteraceae) pene lactones from Distephanus angulifolius. Phytochem- and its In vitro antiplasmodial activity. Molecules, 21, istry, 70, 601–607. 765. 122. Pérez-Victoria JM, Chiquero MJ, Conseil G, Dayan G, 138. Singh SK, Bimal S, Narayan S, Jee C, Bimal D, Das P, Di Pietro A, Barron D, Castanys S, Gamarro F. 1999. Bimal R. 2011. Leishmania donovani: Assessment of Correlation between the affinity of flavonoids binding leishmanicidal effects of herbal extracts obtained from to the cytosolic site of Leishmania tropica multidrug plants in the visceral leishmaniasis endemic area of Bihar, transporter and their efficiency to revert parasite India. Experimental Parasitology, 127, 552–558. resistance to Daunomycin. Biochemistry, 38, 1736–1743. 139. Sirama V, Kokwaro JOwuar B, Yusuf A. 2014. In vitro 123. Picman AK, Rodriguez E, Towers GH. 1979. Formation of anthelmintic bioactivity study of Eclipta prostrata L. adducts of parthenin and related sesquiterpene lactones (whole plant) using adult Haemonchus contortus worms: with cysteine and glutathione. Chemico-biological Inter- A case study of Migori County, Kenya. IOSR Journal of actions, 28, 83–89. Pharmacy and Biological Sciences Ver, 9, 45–53. 124. Pink R, Hudson A, Mouriès MA, Bendig M. 2005. 140. Soejarto DD, Fong HHS, Tan GT, Zhang HJ, Ma CY, Opportunities and challenges in antiparasitic drug Franzblau SG, Gyllenhaal C, Riley MC, Kadushin MR, discovery. Nature Reviews Drug Discovery, 4, 727–740. Pezzuto JM, Xuan LT, Hiep NT, Hung NV, Vu BM, Loc 125. Ramachandran S. 2013. Review on Sphaeranthus indicus PK, Dac LX, Binh LT, Chien NQ, Hai NV, Bich TQ, Linn. (Kot.t.aikkarantai). Pharmacognosy Reviews, 7, Cuong NM, Southavong B, Sydara K, Bouamanivong S, 157–169. Ly HM, Thuy TV, Rose WC, Dietzman GR. 2005. 126. Ramawat KG, Goyal S. 2008. The Indian herbal drugs Ethnobotany/ethnopharmacology and mass bioprospect- scenario in global perspectives, in Bioactive molecules and ing: Issues on intellectual property and benefit-sharing. medicinal plants, Ramawat K, Merillon J, Editors. Journal of Ethnopharmacology, 100, 15–22. Springer, Berlin, Heidelberg, p. 325–347. 141. Steele JCP, Warhurst DC, Kirby GC, Simmonds MSJ. 127. Reale S, Pace L, Monti P, Angelis F De Marcozzi G. 2008. 1999. In vitro and In vivo evaluation of betulinic acid as an A rapid method for the quantification of artemisinin in antimalarial. Phytotherapy Research, 13, 115–119. Artemisia annua L. plants cultivated for the first time in 142. Subhuti D. 2000. Bidens: A popular remedy escapes notice Burundi. Natural Product Research, 22, 360–364. of Western Practitioners. ITM, India. 128. Rodriguez E, Aregullin M, Nishida T, Uehara S, Wrang- 143. Sülsen VP, Puente V, Papademetrio D, Batlle A, Martino ham R, Abramowski Z, Finlayson A, Towers GH. 1985. VS, Frank FM, Lombardo ME. 2016. Mode of action of the Thiarubrine A, a bioactive constituent of Aspilia (Aster- sesquiterpene lactones psilostachyin and psilostachyin C aceae) consumed by wild chimpanzees. Experientia, 41, on Trypanosoma cruzi. Plos One, 11, e0150526. 419–420. 144. Sutherland CJ, Tanomsing N, Nolder D, Oguike M, 129. Rodríguez–Chávez JL, Rufino–González Y, Ponce–Maco- Jennison C, Pukrittayakamee S, Dolecek C, Hien TT, do tela M, Delgado G. 2015. In vitro activity of “Mexican Rosário VE, Arez AP, Pinto J, Michon P, Escalante AA, Arnica” Heterotheca inuloides Cass natural products and Nosten F, Burke M, Lee R, Blaze M, Otto TD, Barnwell some derivatives against Giardia intestinalis. Parasitology, JW, Pain A, Williams J, White NJ, Day NPJ, Snounou G, 142, 576–584. Lockhart PJ, Chiodini PL, Imwong M, Polley SD. 2010. 24 S.K. Panda and W. Luyten: Parasite 2018, 25,10

Two nonrecombining sympatric forms of the human activity of Jasonia glutinosa aerial parts. Pharmaceutical malaria parasite Plasmodium ovale occur globally. Biology, 34, 303–304. Journal of Infectious Diseases, 201, 1544–1550. 157. Wabo Pone J, Fossi Tankoua O, Yondo J, Komtangi MC, 145. Szakiel A, Ruszkowski D, Grudniak A, Kurek A, Wolska Mbida M, Bilong Bilong CF. 2011. The in vitro effects of K, Doligalska M, Janiszowska W. 2008. Antibacterial and aqueous and ethanolic extracts of the leaves of Ageratum antiparasitic activity of oleanolic acid and its glycosides conyzoides (Asteraceae) on three life cycle stages of the isolated from marigold (Calendula officinalis). Planta parasitic nematode Heligmosomoides bakeri (Nematoda: Medica, 74, 1709–1715. Heligmosomatidae). Veterinary Medicine International. 146. Takahashi HT, Novello CR, Ueda-Nakamura T, Filho 140293. BPD, Palazzo de Mello JC, Nakamura CV. 2011. 158. Wang G, Han J, Feng T, Li F, Zhu B. 2009. Bioassay- Thiophene derivatives with antileishmanial activity guided isolation and identification of active compounds isolated from aerial parts of Porophyllum ruderale (Jacq.). from Fructus arctii against Dactylogyrus intermedius Cass. Molecules, 16, 3469–3478. (Monogenea) in goldfish (Carassius auratus). Parasitolo- 147. Talakal TS, Dwivedi SK, Sharma SR. 1995. In vitro and gy Research, 106, 247–255. In vivo antitrypanosomal activity of Xanthium struma- 159. Wanzala W, Takken W, Mukabana WR, Pala AO, rium leaves. Journal of Ethnopharmacology, 49, 141–145. Hassanali A. 2012. Ethnoknowledge of Bukusu community 148. Tasdemir D, Kaiser M, Brun R, Yardley V, Schmidt TJ, on livestock tick prevention and control in Bungoma Tosun F, Ruedi P. 2006. Antitrypanosomal and anti- district, Western Kenya. Journal of Ethnopharmacology, leishmanial activities of flavonoids and their analogues: In 140, 298–324. vitro, In vivo, structure-activity relationship, and quanti- 160. Williams AR, Peña-Espinoza MA, Boas U, Simonsen HT, tative structure-activity relationship studies. Antimicro- Enemark HL, Thamsborg SM. 2016. Anthelmintic activi- bial Agents and Chemotherapy, 50, 1352–1364. ty of chicory (Cichorium intybus): In vitro effects on swine 149. Teixeira TL, Teixeira SC, Silva CV da, Souza MA de. 2014. nematodes and relationship to sesquiterpene lactone Potential therapeutic use of herbal extracts in trypanoso- composition. Parasitology, 143, 770–777. miasis. Pathogens and Global Health, 108, 30–36. 161. Yamamoto ES, Campos BL, Laurenti MD, Lago JH, dos 150. Tiuman TS, Ueda-Nakamura T, Garcia Cortez DA, Dias Santos Grecco S, Corbett CE, Passero LF. 2014. Treatment Filho BP, Morgado-Díaz JA, de Souza W, Nakamura with triterpenic fraction purified from Baccharis uncinella CV. 2005. Antileishmanial activity of parthenolide, a leaves inhibits Leishmania (Leishmania) amazonensis sesquiterpene lactone isolated from Tanacetum parthe- spreading and improves Th1 immune response in infected nium. Antimicrobial Agents and Chemotherapy, 49, mice. Parasitology Research, 13, 333–339. 176–182. 162. Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD, 151. Tobinaga S, Sharma M, Aalbersberg W, Watanabe K, Ribeiro SP, Kallás EG, Rafael-Fernandes M, Santos- Iguchi K, Narui K, Sasatsu M, Waki S. 2009. Isolation and Gomes G, Silva MS, Sessa DP, Lago JHG, Levy D, Passero identification of a potent antimalarial and antibacterial LFD. 2015. The effect of ursolic acid on Leishmania polyacetylene from Bidens pilosa. Planta Medica, 75, 624– (Leishmania) amazonensis is related to programed cell 628. death and presents therapeutic potential in experimental 152. Toyang NJ, Verpoorte R. 2013. A review of the medicinal cutaneous leishmaniasis. PLoS One, 10, e 0144946. potentials of plants of the genus Vernonia (Asteraceae). 163. Yildiz K, Basalan M, Duru O, Gokpinar S. 2011. Journal of Ethnopharmacology, 146, 681–723. Antiparasitic efficiency of Artemisia absinthium on 153. Tran Q Le Tezuka Y, Ueda J, Nguyen NT, Maruyama Y, Toxocara cati in naturally infected cats. Turkish Journal Begum K, Kim H-S, Wataya Y, Tran QK, Kadota S. 2003. of Parasitology, 35, 10–14. In vitro antiplasmodial activity of antimalarial medicinal 164. Yu HW, Wright CW, Cai Y, Yang SL, Phillipson JD, plants used in Vietnamese traditional medicine. Journal of Kirby GC, Warhurst DC. 1994. Antiprotozoal activities Ethnopharmacology, 86, 249–252. of Centipeda minima. Phytotherapy Research, 8, 436–438. 154. Ullah M, Khan MU, Mahmood A, Malik RN, Hussain M, 165. Zahari Z, Jani NA, Amanah A, Latif MNA, Majid MIA, Wazir SM, Daud M, Shinwari ZK. 2013. An ethnobotani- Adenan MI. Bioassay-guided isolation of a sesquiterpene cal survey of indigenous medicinal plants in Wana district lactone of deoxyelephantopin from Elephantopus scaber South Waziristan agency, Pakistan. Journal of Ethno- Linn. active on Trypanosome brucei rhodesience. Phyto- pharmacology, 150, 918–924. medicine, 21, 282–285. 155. Upadhayay N. 2013. Phytosociological documentation of 166. Zhu F, Qin C, Tao L, Liu X, Shi Z, Ma X, Jia J, Tan Y, Cui traditional knowledge of Barleria acanthoides Vahl. Inter- C, Lin J, Tan C, Jiang Y, Chen Y. 2011. Clustered national Journal of Science and Research, 5, 1188–1191. patterns of species origins of nature-derived drugs and 156. Villaescusa L, Diaz AM, Martin T, Gasquet M, Delmas F, clues for future bioprospecting. Proceedings of the Balansard G. 1996. Preliminary screening of antiprotozoal National Academy of Sciences, 108, 12943–12948.

Cite this article as: Panda SK, Luyten W. 2018. Antiparasitic activity in Asteraceae with special attention to ethnobotanical use by the tribes of Odisha, India. Parasite 25,10 S.K. Panda and W. Luyten: Parasite 2018, 25,10 25

An international open-access, peer-reviewed, online journal publishing high quality papers on all aspects of human and animal parasitology

Reviews, articles and short notes may be submitted. Fields include, but are not limited to: general, medical and veterinary parasitology; morphology, including ultrastructure; parasite systematics, including entomology, acarology, helminthology and protistology, and molecular analyses; molecular biology and biochemistry; immunology of parasitic diseases; host-parasite relationships; ecology and life history of parasites; epidemiology; therapeutics; new diagnostic tools. All papers in Parasite are published in English. Manuscripts should have a broad interest and must not have been published or submitted elsewhere. No limit is imposed on the length of manuscripts.

Parasite (open-access) continues Parasite (print and online editions, 1994-2012) and Annales de Parasitologie Humaine et Comparée (1923-1993) and is the official journal of the Société Française de Parasitologie.

Editor-in-Chief: Submit your manuscript at Jean-Lou Justine, Paris https://parasite.edmgr.com/